2-(cyanoaminomethyl)-4,10-dioxo-1,2,3,4,4a,9,9a,10- octahydroanthracenes



United States Patent O 3,514,477 2-(CYANOAMlNOMETI-IYL)-4,10-DIOXO-1,2,3,4,4a, 9,9a,10-CTAHYDROANTHRACENES Lloyd H. Conover, Quaker Hill, Conn., assignor to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Original application June 17, 1966, Ser. No. 558,267, now Patent No. 3,502,696, dated Mar. 24, 1970. Divided and this application Apr. 3, 1967, Ser. No. 627,852

Int. Cl. A61k 27/00; C07c 103/19, 121/66 US. Cl. 260-465 6 Claims ABSTRACT OF THE DISCLOSURE A series of 4,IO-dioxo-l,2,3,4,4a,9,9a,lo-octahydroanthracenes having at the 2-position a formyl, carboxy, carboalkoxy, carbobenzyloxy, carbothioalkyl, carbothiobenzyl chloroformyl, cyanoaminomethyl, or cyanohydroxymethyl group which are useful as intermediates for the synthesis of tetracycline-type antibiotics, as bactericides and/or chelating agents; and methods for their preparation. Tetracyclines are produced by a multistep process beginning with 4,10-dioxo-1,2,3,4,4a,9,9a,10-octahydro-2-anthraldehyde comprising; (1) condensation with acetone cyanohydrin followed by reaction with an amine to give a 2-(cyanoaminomethyl)-4,10-dioxo-1,2,3,4,4a,9, 9a,10-octahydroanthracene; (2) hydrolysis of the nitrile to the corresponding Z-(carboxyaminomethyl)-1,2,3,4,4a, 9,9a,IO-octahydroanthracene; (3) conversion of the acid to a mixed anhydride; (4) acylation of a malonic ester derivative with the mixed anhydride; (5) followed by cyclization of the acyl malonate derivative to a IZa-deoxytetracycline which is then hydroxylated to a tetracycline.

CROSS-REFERENCES TO RELATED APPLICATIONS This application is a divisional of co-pending application Ser. No. 558,267, filed June 17, 1966, which in turn is a continuation-in-part of application Ser. No. 234,511, filed Oct. 31, 1962, which in turn is a continuation-in-part of application Ser. No. 132,287, filed Aug. 18, 1961, both of which are now abandoned.

BACKGROUND OF THE INVENTION This invention relates to a process of preparation of antibacterial agents. More particularly, it is concerned with the discovery of new and novel synthetic routes for the preparation of known as well as new tetracycline products. It is also concerned with the new and useful tetracycline products obtained thereby, as well as with the new intermediates of the process.

The tetracycline antibiotics comprise a group of bio logically active hydronaphthacene derivatives having the following essential structural features. The numbering systern indicated is that employed by Chemical Abstracts.

3,514,477 Patented May 26, 1970 ice Among the biologically active members of this group are those containing the following substituent groups:

Substituents Common name 4-N (CH 2,6-OH,6-C H ,12a-OH Tetracycline. 4-121)Ha)2,5-QH,6OH,6-OH ,12afi-oxytetracyeline:

7-chlorotetraeycline.

6-di0xy-5-oxytetracycline. 4-desdimethylamino-5-oxytetra- SUMMARY OF THE INVENTION The present new processes utilize a unique group of diketotricyclic aldehydes having the following structural formula:

For convenience in illustrating the location of substituent groups the positions of the ring system have been numbered in this formula. The parent compound of the ring system have been numbered in this formula. The parent compound of the series, that is, the unsubstituted product, is 4,10 dioxo-1,2,3,4,4a,9,9a,'10-octahydro-2-anthraldehyde.

In the above formula, X is selected from the group consisting of hydrogen, hydroxy, trifluorom'ethyl, amino, monoand di-lower-alkylamino, alkanoylamino containing 2 to 4 carbon atoms, lower alkyl, alkanoyloxy containing 2 to 4 carbon atoms, and OR wherein R is selected from the group consisting of lower alkyl and benzyl;

X is selected from the group consisting of hydrogen, hydroxy, chloro, lower alkyl, trifluoromethyl, amino, monoand di-lower alkylamino, alkanoylamino containing 2 to 4 carbon atoms, and OR wherein R is lower alkyl;

With the proviso that only one of X and X is selectedfrom the group consisting of amino, monoand di-loweralkylamino, and alkanoylamino containing 2 to 4 carbon atoms;

X is selected from the group consisting of hydrogen, hydroxy, and OR in which R is as previously defined;

A is selected from the group consisting of hydrogen, lower alkyl, and R OCH(R wherein R is lower alkyl and R is selected from the group consisting of hydrogen and lower alkyl.

It should be noted that whereas the X, X and X substituents are arranged in that order in the generic structure I, this representation is for convenience only. In actual practice these groups can occur in any sequence in the benzenoid moiety.

Of course, the compounds of structure I may exist in other tautomeric forms, e.g. the lO-enol form.

The favored compounds of structure I are those of the following formula:

in which X, X R and A are as above-described. The preferred compounds are those in which the X and X groups are at the 7- and 8-positions or the 8- and 7-positions of Formula 1-A. These compounds are preferred since they are useful in the preparation of known tetracyclines as well as new and useful tetracycline derivatives not previously described.

Compounds of structure I are particularly useful in synthesizing 6-deoxytetracycline, 6-dexoy-6 demethyltetracycline and various novel antimicrobial agents bearing structural similarities to the known tetracycline antibiotics. Thus, Structure I compounds may be transformed, by a number of alternative synthetic sequences, to tetracyclines having the formula X t no X2 ('i (5111 Y4 (XXIII) where X, X X and A are as previously defined. Additionally, these substituents may be replaced, in the final tetracycline or in the intermediates, by other valuable groupings, according to procedures described hereinafter. Thus, X, X and X may be transformed to hydroxy, nitro, cyano, bromo, carbalkoxy, hydroxyalkyl, alkyl sulfonyl, halo sulfonyl, alkyl sulfinyl, and sulfamyl, and A may be transformed to amino, monoand dialkylamino, =CHR and -CH(R )OH, by appropriate reactions, as will be later discussed.

In the above formula, R and R when taken together with the nitrogen atom to which they are attached form a nitrogen heterocyclic ring selected from the group consisting of piperazino, piperidino, mor-pholino, thiomorpholino, pyrrylo, pyrrolidino, and Z-(lower carbalkoxy)pyrrolidino;

R and R are each selected from the group consisting of hydrogen, alkanoyl containing 1 to 4 carbon atoms, and CH B wherein B is selected from the group consisting of hydrogen, lower alkyl and monosubstituted lower alkyl, said substituent 'being selected from the group consisting of hydroxy and lower alkoxy;

Provided that only one of R and R is selected from the group consisting of alkanoyl containing 1 to 4 carbon atoms;

and Y, is selected from the group consisting of cyano and wherein D is selected from the group consisting of hydrogen and lower alkyl.

Several alternative procedures are available for the preparation of the tetracyclines of Structure XXIII from aldehydes I. The choice of a particular route for the preparation of a given tetracycline will be influenced by availability of materials, yields of products throughout the sequence, and similar economic factors. The conditions employed in each of the reactions can, unless otherwise indicated, be varied within the skill of the art.

DETAILED DESCRIPTION OF THE INVENTION The various alternative reaction sequences for the preparation of tetracyclines XXIII via aldehydes I, and other novel intermediates utilized in these alternatives sequences, are summarized in Flow Sheet I.

A I A -COR2 X1 X2 II A NR R7 X I X2 H ll A RsRI X I Y Y4 X2 ll 0 O A NR R X I X1 XXIII X2 0 OH O FLOl/V SHEET I In the reaction sequences depicted in Flow Sheet I, X, X X A, R R and Y; are as previously defined;

B is selected from the group consisting of lower alkyl, benzyl and mercaptoethyl;

D is selected from the group consisting of cyano and C02 wherein Z is selected from the group consisting of hydroxy, lower alkoxy,

and O (CO)OR wherein R is lower alkyl;

R is selected from the group consisting of hydroXy, lower alkoxy, benzyloxy, and halo;

Y is selected from the group consisting of hydrogen, cyano and lower carbalkoxy.

Reaction sequences depicting the conversion of aldehydes I to tetracyclines in greater detail are provided 1n Flow Sheet 2.

CHO

X2 ll 1 O NRsR (XVI) )(CO)ORs X 2 ll 0 (XVII) O X\' O xii 1 X? at (XVIII) AK-OH t...

(XIX) FLOW SHEET 2 AUCHO Y OCH | AOA 4 a where R and R are hydrogen the product can be obtained by reaction of the aldehyde with a mixture of ammonium chloride and sodium cyanide in ammoniacal aqneuos alcohol. The aminonitn'les are converted to the aminoacids (Y =COOH) by acid hydrolysis or by prolonged refluxing in 5% NaOH in the presence of ZnCl XVI- XVII: is the formation of a mixed anhydride with a lower alkyl chlorocarbonate as described in the Journal of the American Chemical Society, vol. 75, p. 638 (1953) and the Journal of Organic Chemistry, vol. 22, p. 248 (1957).

XVII- XVIII: is the acylation of a malonic ester derivative with XVH. Suitable malonic derivatives include malonic ester, cyanoacetic ester, malonodinitrile, malonic ester half amide, etc. The malonic diester, cyanoacetic ester, malonic ester half amide, including N-alkylated amides and especially the magnesium salt of ethyl t-butylmaloamate etc., with the mixed anhydride produces the malonate. Reaction is conducted in a suitable solvent system such as chloroform, toluene, benzene, diethylether, acetonitrile, dimethylformamide, nitromethane, dioxane, tctrahydrofuran, ethers of ethyleneglycol and diethyleneglycol at from about 5 to about 35 C. for periods ranging from 25 minutes to up to 3 days. When X is (CO)OR the malonic acid derivative is employed as a magnesium enolate according to the procedure of Tarbell and Price (J. Org. Chem, Loc. cit.) (R =lower alkyl, benzyl).

Where Y =N-alkyl carboxamido, treatment of XVIII with sulfuric acid (e.g. H 80 yields the corresponding unsubstituted car boxamide.

XVVIII XIX: represents ring closure by base-catalyzed acylation. Where Y =CN the l-imido group which results is hydrolyzed with aqueous acid to the keto group. Where Y and Y are both hydrogen, base-catalyzed acylation with a dialkyl carbonate provides XIX (Y =H).

Compounds of structure XIX wherein Y; is other than cyano 0r carboxamido may be converted to compounds wherein Y =CN or CONH by a variety of routes. Where the C substituent is H (Y H), treatment with an alkyl or acyl isocyanate in the presence of sodium hydride or other base (triethylamine, alkali metal alkoxides, sodamide, 1,4-diaza[2,2,2]bicyclooctane) introduces a 2-N-substituted carboxamido group. In the case of an acyl isocyanate, the resulting Z-N-acyl carboxamido group is readily hydrolyzed to a Z-cahboxamido group by methanolic ammonia; while in the case of a secondary or tertiary alkyl isocyanate, e.g. t-butyl isocyanate the resulting 2-N-alkyl carboxamido group is converted to the 2-carboxamido group by dealkylation with concentrated mineral acid and water. The carboxamido group may also be introduced into compounds of Formula XIX by treatment with carbamyl chloride or an N-alkyl carbamyl chloride under basic conditions, e.g. in the presence of triethylamine, or other base as given above. Where a secondary or tertiary N-alkyl carboxamide is converted to an unsubstituted carboxamide by treatment with mineral acid as previously discussed.

The reactions of isocyanates and carbamyl chlorides are generally carried out at temperatures of from about 0 to about 70 C. Most reactions proceed satisfactorily at room temperature after an initial cooling period which serves to moderate the reaction during the mixing of the reactants. Solvents such as dimethyl sulfoxide, toluene, dioxane, tetrahydrofuran, acetonitrile, ethers of ethyleneand diethyleneglycol and especially dimethylfortnarnide are suitable for the reaction. The reaction time varies from about minutes to 24 hours depending upon the reactants.

Additionally, thet carboxamide group may be introduced at the 2-position of these compounds by heating with urea under basic conditions. For example, the reaction may be carried out in dimethyl-formamide solution under the influence of triethanolamine at temperatures ranging from 80 C. to the boiling point of the solvent. The reaction period varies with the structure of the reactant. However, periods of from about 5 minutes to one hour are generally satisfactory.

In lieu of this procedure, fusion with urea at about 130 C. for from to 45 minutes under nitrogen serves to introduce a carboxamide group at C2. (Scarborough, J. Org. Chem. 26, 3717 (1960) Additionally, compounds in which hydrogen is at C2 may be treated with lower alkyl halocarbonates to introduce carbalkoxy under conditions similar to those described above for introducing the carboxamide group via carbamyl chlorides. Further, ethyl ortho formate under acid conditions introduces a formyl group at C2. The aldehyde function thus produced can be subjected to typical carbonyl reactions.

Compounds of structure XIX in which hydrogen is at C2 are converted to corresponding compounds in which C2 bears cyano by reaction with ethyl chloroximinoacetate in the presence of an acid acceptor, e.g. sodium carbonate or triethylamine, followed by hydrolysis of the thus produced 2,3-tetracycline 4',5 isoxazole-3-carboxylic acid ethyl ester to the corresponding 3'-carboxylic acid which is decarboxylated and converted to the nitrile product by treatment with copper and ammonia. A further related method comprises the reaction of chlorine free cyanogen chloride with compounds of structure XIX.

Conversion of the 2-cyano group to a carboxamido group is accomplished by the method described in U.S. Pat. 3,029,284, issued Apr. 10, 1962 wherein is described the conversion of tetracycline nitriles to the corresponding carboxamide by the Ritter Reaction followed by dealkylation of the resulting N-alkylated carboxamide with concentrated mineral acid and water.

Where Y =carbalkoxy, conversion to the corresponding carboxamido compounds is accomplished by ammonium formate fusion followed by hydrolysis, but the yield in this instance is usually lower.

In the above sequences, many of the indicated steps are carried out by standard procedures known to those in the art, e.g. hydrolysis, esterification, acylation, etc.

l2a-hydroxylation may be accomplished by known procedures such as described in J.A.C.S. 81, p. 4748 (1959). A preferred method of 12a-hydroxylation is the method described in U.S. Pat. 3,188,348, issued June 8, 1965, wherein is described the hydroxylation of certain metal chelates of 12a-deoxytetracyclines. The advantage of this latter process lies in the fact that the hydroxyl group is introduced cis to the hydrogen at position 4a of the tetracycline nucleus.

A variety of 4-aminotetracyclines are prepared according to the present invention by substituting various primary or secondary amines, as well as ammonia, for dimethylamine. Suitable amines include other dialkyl amines, e.g. methyl, ethyl, propyl, etc. amines; aralkyl and alkaryl amines, and N-alkyl derivatives thereof, e.g. N-methylaniline, benzylamine; heterocyclic amines, e.g. pyrrolidine, morpholine, aminopyridines and N-alkyl derivatives thereof. Further, hydroxyalkyl substituents on the nitrogen, where protected for some of the reaction steps by ether formation or acetylation, as discussed below, may subsequently be regenerated by HBr cleavage or hydrolysis.

When the substituents of the present compounds are hydroxy or amino, the use of a blocking group is sometimes advantageous in obtaining high yields during their preparation. Especially useful blocking groups are acyl, benzyl, tetrahydropyranyl, methoxymethyl, methyl and ethyl radicals. Benzyl ethers are particularly easily reduced to hydroxyl groups. Hydroxyl groups are conveniently protected during basic reaction steps by prior conversion to the tetrahydropyranyl ether, which is easily re-hydrolyzed under mildly acidic conditions. Acyl groups which may be used include the acetyl, propionyl, butyryl, benzoyl and the like. The lower alkyl blocking groups are preferred because of the ease with which these compounds are prepared.

When desired, the above mentioned blocking groups, i.e. enol ether radicals, may be removed. The enol radicals are hydrolyzed by treatment with aqueous acid as is Well known by those skilled in the art. When the ether radical is benzyl, hydrogenolysis over noble metal catalyst may also be used.

The new compounds described herein are useful as chelating, complexing, or sequestering agents. The complexes formed with polyvalent metal ions are particularly stable and usually quite soluble in various organic solvents. These properties, of course, render them useful for a variety of purposes wherein metal ion contamination presents a problem, e.g. in metal extraction and biological experimentation, as well as in various organic systems such as saturated and unsaturated lubricating oils, hydrocarbons, fatty acids and waxes, wherein metal ion contamination accelerates oxidative deterioration and color formation. They are also useful as metal carriers and in analysis of polyvalent metal ions which may be complexed and extracted by means of these reagents. Other uses common to sequestering agents will also be apparent.

In addition, the compounds of Flow Sheet I are especially valuable as intermediates in chemical synthesis. They are particularly useful in synthesizing 6-deoxytetracycline, 6-deoxy-6-demethyltetracycline and various novel tetracyclines. Many of the herein described compounds, especially those containing one or more hydroxyl groups in the benzeneoid moiety, are useful as antibacterial agents in their own right.

In order to synthesize biologically active tetracyclines, it is necessary to employ intermediates in which the hydrogen atoms at the 9a and 2-positions of the anthracene ring (corresponding to the 4a and Sa-positions of the tetracycline nucleus) are in the cis arrangement. For example, preferred compounds are depicted by the following formula (syn. compounds) A H X G X2 II N O O in which G is a substituent other than hydrogen, as contrasted with anti compounds of the formula:

In general, syn and anti compounds are separable by virtue of differences in physical properties, e.g. differences in solubility in various solvents. Usually, fractional crystallization permits ready separation. The syn and anti compounds are diastereoisorners.

It is a particular advantage of the novel diketo tricyclic octahydroanthraldehydes of the present invention that, by virtue of the activating influence. of the aldehyde oxygen, they equilibrate to the predominately cis configuration in the course of preparation. This enables the synthesis to proceed in stereospecific fashion without the loss of material that would otherwise be entailed in the separation of syn and anti compounds.

It is recognized by those in the art that, when such compounds have an asymmetric center in the substituent G, they exist as two diastereoisorners which, as previously mentioned, may be separated by fractional crystallization for each of the syn and anti compounds. Of course, as is known, diastereoisorners are racemic modifications consisting of two structures which are mirror images (optical antipodes). The racemic modifications may be resolved according to standard procedures. In the present process it is preferred, however, to utilize the diastereoisorners of the syn compounds since changes in configuration may occur during the various procedural steps of the total synthesis to tetracycline compounds, thus necessitating costly and time-consuming resolution procedures. The syn diastereoisorners are converted to tetracycline products which consist of the normal tetracyclines and their 4- epimers which are separable by known procedures. Of course, the 4-epitetracyclines are useful in that they are converted to normal tetracyclines by known procedures.

The diketo tricyclic aldehydes of structure I may be prepared by several useful procedures. They may, for example, be synthesized from the triketo tricyclic esters of Structure IV (the synthesis of which is described hereinafter) by the reaction sequences illustrated in accompanying Flow Sheet 3. In this sequence, X, X X A, B and R are as previously defined; and R is lower alkyl or benzyl. The reactions shown are as follows:

IV XV: is reduction of the 3-keto group by standard procedures. This may be efiected in stepwise fashion: the 3-keto group being first reduced to hydroxyl under mild conditions, e.g. with zinc dust and glacial acetic acid or with sodium borohydride; the resulting alcohol then being converted to the formate by treatment with acetoformic anhydride; and the formate in turn being reduced to tricyclic diketo ester XV with zinc dust and formic acid or by hydrogenation with palladium. Alternatively, the reduction IV-XV may be effected in one step with zinc and acetic acid under more vigorous conditions.

IV XX: is a conversion of the 3-keto group to the ethylene dithioketal by treatment with ethanedithiol under esterifying conditions, i.e. by reflux in an azeotroping solvent such as toluene in the presence of a catalytic amount of acid catalyst.

XX XV: is a reduction of the dithioketal by treatment with Raney nickel according to standard procedures. This process also leaves the 2-carbalkoxy group intact. The product may be converted to the corresponding acid by standard acid hydrolysis, and the acid in turn converted to the acid chloride ('R =halo) by standard reactions such as treatment with phosphorus pentachloride.

XV I: represents preparation of the diketo tricyclic aldehyde by reduction of XV in which R; is halo. The Rosenmund reduction, i.e. hydrogenation with a poisoned palladium catalyst, is appropriate for this step. Alternatively, the reduction may be conducted with lithium-tri-tbutoxyaluminohydride (as described in the Journal of the American Chemical Society, vol. 78, p. 252, 1956).

XV XXI: is a transesterification of the diketo tricyclic ester (R =lower .alkoxy or benzyloxy) with mercaptan HSB to form the 2-carbothiolic ester.

XXI- 1: is the reduction of the carbothiolic ester group to the aldehyde by treatment with Raney nickel under standard conditions.

X2 II II A X I COzRt X1 51 J X z t t COR: X1 l COSBz X2 (I) ll CHO X2 H II 'FLOW SHEET 3 The diketo tricyclic aldehydes of structure I may also be prepared by the synthetic sequences indicated in attached Flow Sheet 4 in which X, X X A, and R are as previously defined and D is COR or cyano. The preparation of starting compounds of structures III and XII will be described hereinafter.

III+XXIIz is an alternative route to the dicarboxy propyl tat-tetralone via the base-catalyzed alkylation of a 2-(fl-carboalkoxyethyl)-4-tetralone (D =lower carboalkoxy) or a Z-(B-cyanoethyl) tetralone (D =CN) with an alkyl haloacetate. For this reaction it is advisable to first convert the tetralone to a ketal, egg. by treatment with ethylene glycol, B-mercaptoethanol or ethanedithiol under standard conditions. Diester product XXII may be converted to the corresponding dibasic acid where required, by standard hydrolysis procedures.

XXII- XV: represents ring-closure of a-tetralone XXII, as a diester (D =lower carbalkoxy, R =lower alkyl) or an ester-nitrile (D =CN, R =lower alkyl) by a base-catalyzed acylation reaction, to form the diketo tricyclic ester or nitrile XV.

III- IV: represents condensation with oxalic ester in the presence of strong base, as further discussed hereinafter in conjunction with the synthesis of compounds III and IV.

IV- XV: represents reduction of the 3-keto group by the procedures described in conjunction with Flow Sheet 3.

XV I: may be effected, where D =lower carbalkoxy, by the procedures described in conjunction with Flow Sheet 3. Alternatively, where D =CN, direct reduction to the aldehyde may be effected, e.g. with lithium triethoxyaluminohydride, or with disobutyl aluminum hydride as described in Proc. Acad. Sci. USSR, Chemistry Section, pp. 879-81 (1957). In addition, ester XV (D '=lower carbalkoxy) is readily converted to the corresponding amide, the latter dehydrated to nitrile XV (D =CN), and the nitrile in turn reduced to aldehyde I, by standard procedures.

A A X X I D3 M /\f\/ X1 I Xi X COZR! X \H/ 2 I) 2 O (XXII) (III) A A X I (I) 4- X1 1 X1 O N V X2 II II X2 II II O O O (XV) (IV) FLOW SHEET 4 In the foregoing reaction sequence it is often most convenient to introduce the X, X and X groups by employing the appropriately substituted benzoyl succinate XII as starting material. Syntheses for a variety of these succinates are described hereinafter, and others may be readily devised by those skilled in the art.

In commencing the sequence with a substituted benzoyl succinate or benzyladipate it is essential that an ortho ring position be unsubstituted, since cyclization to form the center ring of the hydroanthraldehyde occurs at this position. For the preparation of the preferred aldehydes of structure 1A, which bear an OR substituent in the 5-position, the position of the benzene ring be tween the OR group and the keto group in the starting benzoyl succinate should be unsubstituted, to provide for the subsequent ring closure. On the other hand, it is preferred to have a substituent in what corresponds to the 8-position of aldehyde I, since this precludes cyclization to that position in competition with the desired cyclization. A CF lower alkyl, or acylamino group can be conveniently carried in this position from the outset. Alternatively, an 8-substituent may be introduced during the reaction sequence, prior to the cyclization.

The discussion which follows describes the synthesis of starting compounds III, IV and XII for Flow Sheets 3 and 4.

The starting compounds of structure III and IV are prepared according to the following procedure:

A A X I /\/OORz X I COR2 XHQ Xi I X2 0 CR2 X2 I II 0 III lwhera R2=OR1 where R2=OII A A X I COzH X I -CO2R1 X1 X1 1 O 02R: :0 X2 I II 2 l I 0 O O O (IIIa) (IV) In the above formulae, X, X X A, R and R are as previously described with the exception that substituent X is preferably not a nitro group since this group deactivates the ring of compounds of structure II in the ring closure reaction to those of structure III. Alternatively, the corresponding nitriles (e.g. Where COR is replaced by CN may be used in the case of m-hydroxyor alkoXy-benzyl compounds of structure II. Further, at least one of the two positions of the benzenoid ring ortho to the diester side chain should be available for the ring closure of compounds of structure II to the structure III compounds. If desired, halogen (C1 or Br) may be introduced into compounds of structure II and structure III in which at least one of the benzenoid substituents is hydrogen by direct halogenation with a chlorinating or brominating agent or by other methods generally employed for halogenation of an aromatic ring. A variety of such agents are known to those in the art and include phosphorus pentachloride and pentabromide, sulfuryl chloride, N-chloro or bromoalkanoamides, e.g. N-chlorand N-bromacetamide; N-chl0ro (or bromo) alkanedioic acid imides, e.g. N-halosuccinimide; N-halophthalimide; chlorine; bromine; N-haloacylanilides, e.g. N-bromoacetanilide, propionanilide and the like; 3- chloro-, 3-bromo, 3,5-dichloro and 3,5-dibromo-5,5-dimethylhydantoin; pyridinium perbromide and perchloride hydrohalides, e.g. pyridinium perbromide hydrobromide; and lower alkyl hypochlorites, e.g. t-butylhypochlorite.

Alternatively, compounds of structure IV may be prepared by the following sequences:

X2 COORI II o The ring closure of compounds II to III or VI to IV is accomplished by any of the commonly employed methods for such reactions which generally involve the use of a dehydrating or dehydrohalogenating cyclization agent. With compounds of structure II, a preferred method When R is OH or alkoxy involves treatment of the starting compound with such ring closure agents as hydrogen fluoride or polyphosphoric acid. When R is halogen, a Friedel-Crafts catalyst, of course, should be employed, e.g. aluminum chloride. m-Hydroxyor alkoXy-benzyl compounds of structure II having CN in place of COR lend themselves to the Hoesch synthesis (Berichte, 48, 1122 and 50, 462) wherein treatment with dry hydrogen chloride in the presence of zinc chloride leads to imine formation, and hydrolysis of the latter provides the tetralone keto group.

The condensation of compounds II or III in which R is CR with oxalic ester are efiected by the general methods for ester condensation reactions of this type. Usually the reaction is carried out in the presence of a strong base such as alkali metal, alkali metal alkoxides and hydrides, sodamide and the like. If the starting compound in the oxalate condensation contains free hydroxy or amino it is preferred to block such groups by alkylation or acylation by known procedures. After the reaction is completed, the blocking groups may be removed, if desired. Cleavage of the ether linkage or other blocking groups by any of the general methods, e.g. treatment with mineral acid such as concentrated hydrobromic or hydriodic acid, or, when R is benzyl, hydrogenolysis, gives a free hydroxy group in the benzenoid portion.

The starting compounds of the above described processes, i.e. compounds of structure II are prepared by the following sequence of reactions:

COHal X1 i X1 I ORr R1 (LE1 R1 VII) V X X X1 X1 I 0R O H (VIII) (IX) X C OzRg Xi l II F LOW SHEET In the above sequence, R is lower alkyl or benzyl; R is hydrogen, lower alkyl or benzyl; and B is hydrogen and hydroxyl. Further, in this sequence a lower alkyl group can be present in the starting diether at the 4- position of the aromatic ring if desired to produce 3- benzyl-4-(lower alkyl) substituted adipic acid derivatives (II).

The first of these reactions for the preparation of compounds of structure VH is by means of Friedel-Crafts reaction, e.g. A1Cl in carbon disulfide. The conversion of compounds of structure VH to those of VHI in which A and B are hydrogen is by catalytic reduction, e.g. over copper chromium oxide or noble metal, e.g. palladium catalyst at from atmospheric to superatmospheric pressures of hydrogen gas; where A is alkyl and B hydroxyl, by reaction with a suitable Grignard reagent, e.g. AMg Halogen; where A is alkyl or hydrogen and B is hydrogen, by reduction, i.e. hydrogenolysis, of corresponding compounds in which B is hydroxyl. From VIII to IX is a standard ether hydrolysis, e.g. concentrated hydrobromic acid. From 1X to X is an ozonolysis reaction giving rise to the dienedioic acid (R =H) which on hydrogenation over a noble metal catalyst, e.g. palladium, palladium on carbon, platinum, platinum oxide, etc., gives compounds of structure II. From VIII to X represents the ozonolysis reaction as applied to the diether to produce X in the form of a diester. In the hydrogenation reaction, compounds of structure X may be used as the free acids or corresponding benzyl or lower alkyl esters to provide corresponding products of structure H. Of course, benzyl esters may undergo concurrent hydrogenolysis to the free acids.

In the described reaction sequences, where aromatic halo substituents are present, care should be taken to avoid prolonged hydrogenations which may result in the removal of the halogen atom. The possibility of halogen removal may be minimized by the use of a lower alkanoic acid, e.g. acetic or propionic, as solvent for the reaction. Of course, if removed, halogen may be reintroduced, if desired, by the methods hereinbefore described. 'Free amino groups are protected by acylation. In the ozonolysis reaction to form compounds of structure X it is possible to employ as starting compounds those of structure IX in which there are adjacent hydroxyl groups in the benzene ring containing X, X and X as substituents, since such structures are susceptible to the oxidation reaction. Similarly, care must be taken to protect adjacent hydroxyl and amino groups as by alkylation or acylation in order to avoid formation of quinone and irnine type products. Where X, X or X are alkyl ether groups and R '=benzyl, step VIII- IX may be accomplished selectively by hydrogenolysis of the benzyl ether groups.

The benzyl keto group of compounds VII may be subjected to the Well known Wittig reaction to introduce an alkylidene, aldehyde, alkoxyalkyl or hydroxyalkyl group in the tetracycline 6-position, as discussed in conjunction with compounds IIa.

Compounds of structure II are also prepared by the following sequences of reactions:

0 X I 0 2 X1 I XII X H C 2 1 C 02R X1 XI XIV O X ll CO2R 2 XIII FLOW SHEET 6 The conversion of compounds of Formula XI to those of XII is a Claisen-type condensation of the lower alkyl ester of XI with succinic acid diesters to provide Formula XII compounds. The conversion of compounds of Formula XI to XIII is similarly a Claisen condensation using acetic acid esters. The conversion of compounds of Formula XIII to XII is by alkylation reaction with a monohaloacetic acid ester, and the conversion of XIV to Ha is such an alkylation followed by hydrolysis and decarboxylation. The preparation of compounds of Formula XIV from those of Formula XIII is by standard alkylation procedures, preferably using an acrylic acid ester of the formula H C=CHCO R or the corresponding nitrile. This conversion may also be eifected by alkylation with a fi-haloacid derivative of the formula Halogen-CH CH CO R or the corresponding nitrile. Each of these reactions are effected under standard conditions known to those skilled in the art, e.g. in a reaction-inert solvent in the presence of a base such as Triton B (benzyltrimethylammonium hydroxide), sodamide, sodium hydride and their obvious equivalents.

The conversion of compounds of Formula XII to those of 11a is by known standard reactions, e.g. by reaction of Formula XII compounds with a corresponding acrylic acid ester of the formula H C=CHCO R It may also be effected by alkylation with a fl-halo-alkanoic acid of the formula Halogen-CH CH CO R or the corresponding nitrile. Hydrolysis and decarboxylation of these compounds gives structure 110 compounds. In the conversions XIV Ila and XII-Ha omission of the hydrolysis and decarboxylation steps permits retention of the carbalkoxy group (R =lower alkyl) in the Sn position of the final tetracycline.

The conversion of structure IIa compounds to those of structure II is brought about by reactions as previously described for preparing structure VIII compounds. Thus, for example, the keto group of structure IIa compounds may be reduced to structure II (A=H), e.g. by palladium-catalyzed hydrogenolysis or by the well known Clemmensen procedures with zinc and HCl. Similarly, re action of Ila with a Grignard reagent permits replacement of the keto oxygen with an alkyl and a hydroxyl group, providing an intermediate for further reactions, i.e. hydrogenolysis of the hydroxyl group to provide 11 (A=alkyl).

An amino group may also be introduced in place of the keto carbonyl oxygen of compounds of structures XIV, VII and Ha by reduction of the corresponding oxime or hydrazone or by reductive amination of the keto carbonyl group over noble metal catalysts.

A modification of the present invention provides a further means of introducing a variety of substituents in positions corresponding to the 521, and 6-position of the tetracycline nucleus. This involves formation of the secondary alcohol corresponding to structure IIa compounds represented by the formula:

I CO2R1 OR by partial reduction of the corresponding ketone with sodium borohydride or by hydrogenation over palladium catalyst until only one molar equivalent of hydrogen is taken up. Compounds of structure V may be subjected to replacement reactions. They may, for example, be converted to the corresponding tosylate which, upon treatment with ammonia or a primary or secondary amine, affords an alternative method for introducing an amino group in the 6position of the final tetracycline. The tosylate also affords a means for introducing a cyano or group at the tetracycline 6-position. The secondary alcohol V may also be dehydrated to the corresponding unsaturated compound (by treatment with HF) and the unsaturated compound reduced to the corresponding benzyl derivative. Compounds of structure V are also intermediates for the preparation of 6-de1nethyltetracyclines.

Other modifications of the present invention provide means for introducing an alkylideno group in the 6-position of the tetracycline nucleus. The benzoyl keto group of compounds of structure Ila may be subjected to the previously discussed Wittig reaction in the same manner as Compounds VII.

X I I X sofl) (R4) /\/C O2R1 /\/C 02111 X2 CO2R1 X2 CO2R1 by treatment with the ylid prepared from a chloroether of the formula R CHClOR (where R is lower alkyl and R is hydrogen or lower alkyl). The necessary chloroethers are obtained by treatment of an aldehyde acetal of the formula R CH(OR with an acid chloride, as described by Post (J. Org. Chem. I, p. 231, 1936).

The products of the above reaction may in turn be hydrogenated with noble metal catalysts:

R300 (R4) RBOCH (R4) X\ H /\/CO2Rr X N (302111 X2 CO'gRt X2 062111 Subjecting the reduction products to the further synthetic sequences illustrated herein yields tetracyclines having a 6-CH(R )OR substituent. Treatment of such tetracyclines with liquid hydrogen fluoride results in the elimination of a mole of alcohol R OH and provides tetracyclines having a =CH(R group at the 6-position. The latter treatment is, for example, conveniently effected after the introduction of the 12a-hydroxy group. Alternatively, treatment of such tetracyclines having a 6-CH(R )OR substituent with HBr converts this group to -CH(R )OH with concurrent hydrolysis of any ether groups in the aromatic D-ring.

The products of the Wittig reaction may also be hydrolyzed, e.g.

X2 COzRr and the resulting aldehyde group in turn converted by catalytic hydrogenation to a hydroxymethyl group. The latter may be carried through the subsequent reactions of the synthetic sequence with its free hydroxyl group, or preferably, in the form of a lower alkyl ether.

The described procedures are adaptable to the preparation of a variety of tetracycline molecules, as follows:

For introduction of aromatic nitro groups, the given compound, e.g. tetralone III, is nitrated by standard procedures, such as treatment with nitric acid-acetic anhydride-acetic acid mixtures, or nitric-sulfuric acid mixtures. Those in which X is halogen, cyano, halo sulfonyl nitro or other such groups may be prepared by Sandmeyer reaction of the corresponding diazonium salt with suitable salt reagents (Cu Cl Cu Br KI, etc.).

The diazonium salt is obtained by diazotisation of the amino compound, which may in turn be prepared by reduction of the corresponding nitro compound by conventional means, e.g. chemical reduction with active metals (Sn) and mineral acids (HCl) or catalytic hydrogenation e.g. with nickel catalyst at superatmospheric pressure. Aromatic cyano groups may be further converted to carboxy or carbalkoxy groups Where desired by standard hydrolysis and esterification.

The amino group may also be introduced into the benzenoid ring, e.g. in compounds of structure II having a phenolic hydroxyl group, by coupling with aryldiazonium salts such as benzene diazonium chloride or the diazonium salt of p-aminobenzenesulfonic acid, followed by reduction of the resulting phenylazo compound, e.g. by catalytic hydrogenolysis with noble metal catalysts.

As has been previously pointed out, normal discretion must be employed in subjecting certain of the substituted intermediates to the herein described reaction steps. In the base condensation reactions the presence of a substituent having an active hydrogen (e.g. a hydroxyl or amino group) will necessitate the use of an additional mole of the sodium hydride or other base. The presence of more than one such substituent per molecule is preferably avoided in these reactions, e.g. by the use of protective ether groups as previously described. The considerations apply to Grignard reactions and hydride reductions. Hydroxyl groups can be subsequently regenerated from their ethers by conventional hydrolytic procedures such as treatment with hydrogen bromide. Similarly, protective benzyl ether groups can subsequently be hydrogenolyzed to obtain hydroxyl groups where desired.

In the reduction of diketo tricyclic acid chloride XV to aldehyde I, the lithium-tri-t-butoxyaluminohydride procedure described may be substituted for the Rosenmund palladium reduction. Similarly, in the reduction of benzoyl adipate IIa or benzophenone VII to the corresponding benzyl derivatives II and VIII, chemical reduction with amalgamated zinc and HCl by the well known Clemmensen procedure may be employed in place of catalytic hydrogenolysis. Any ester groups which may be present in the molecule may be concurrently hydrolyzed in the Clemmensen procedure, and reesterification may therefore be necessary.

Alternative routes or procedures can be selected in place of the Clemmensen reduction. Thus, in the reduction of benzoyl adipate Ila to corresponding benzyl derivative II, the three-step procedure previously referred to is an appropriate alternative to direct reduction; i.e. (1) conversion of the keto group to hydroxyl, e.g. with sodium borohydride or by mild reduction at room temperature with palladium on carbon in alcohol or other neutral solvent; (2) conversion of the resulting alcohol to the unsaturated compound by dehydration in anhydrous hydrogen fluoride; and (3) rapid hydrogenation of the resulting double bond, e.g. with palladium at room tem perature and moderate hydrogen pressure, until one mole of hydrogen has been consumed. Another alternative reduction procedure which is suitable is the Wolf-Kishner reaction (Annalen, 394, 90, 1912 and J. Russ. Phys. Chem. Soc., 43, 582, 1911) wherein the benzoyl derivative is converted to a hydrazone, and the latter is in turn reduced to the corresponding benzyl derivative by heating with a base such as sodium ethoxide.

The present invention provides a means of synthesizing tetracycline compounds including 8-substituted and other valuable new tetracyclines, not previously described, which are therapeutically useful by virtue of their antimicrobial activity.

Some of the new tetracyclines of the present invention are homologs, isomers or closely related analogs of known tetracyclines. Many of the new tetracyclines are distinguished from prior art compounds by their possession of important and desirable properties, such as extended in vitro and in vivo antibacterial spectra, activity against organisms which have inherent or acquired resistance to known antibiotics, rapid absorption, sustained blood levels, freedom from serum binding, preferential tissue distribution at various parts of the body (e.g. kidney, lung, bladder, skin, etc.) which are sites for infection, sustained stability in a variety of dosage forms, resistance to metabolic destruction, broad solubility, and freedom from objectionable acute and cumulative sideeffects. The new tetracyclines are useful in therapy, in agriculture, and in veterinary practice both therapeutically and as growth stimulants. In addition, they may be employed as disinfectants and bacteriostatic agents, in industrial fermentations to prevent contamination by sensitive organisms, and in tissue culture, e.g. for vaccine production.

The various new tetracyclines of the present invention which do not share the antibacterial activity of the known tetracyclines are valuable intermediates in the preparation of other compounds of classes known to contain biologically active members. Thus, the D-ring can be nitrated directly and the nitro derivative reduced catalytically to an aminotetracycline. Further, the tetracycline products of this invention can be halogenated by known methods at the 11a, or in the case of a 7-unsubstituted tetracycline, in the 7,11a-positions by treatment with such halogenating agents as perchloryl fluoride, N-chlorsuccinimide, N- bromsuccinimide and iodobromide.

The present invention embraces all salts, including acid-addition and metal salts, of the new antibiotics. Such salts are formed by well known procedures with both pharmaceutically acceptable and pharmaceutically unacceptable acids and metals. By pharmaceutically acceptable is meant those salt-forming acids and metals which do not substantially increase the toxicity of the antibiotic.

The pharmaceutically acceptable acid addition salts are of particular value in therapy. These include salts of mineral acids such as hydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g. p-toluenesulfonic acids, and the like. The pharmaceutically unacceptable acid addition salts, while not useful for therapy, are valuable for isolation and purification of the new substances. Further, they are useful for the preparation of pharmaceutically acceptable salts. Of this group, the more common salts include those formed with hydrofluoric and perchloric acids. Hydrofluoride salts are particularly useful for the preparation of the pharmaceutically acceptable salts, e.g. the hydrochlorides, by solution in hydrochloric acid and crystallization of the hydrochloride salt formed. The per-- chloric acid salts are useful for purification and crystallization of the new products.

Whereas all metal salts may be prepared and are useful for various purposes, the pharmaceutically acceptable metal salts are particularly valuable because of their utility in therapy. The pharmaceutically acceptable metals include more commonly sodium, potassium and alkaline earth metals of atomic number up to and including 20, i.e. magnesium and calcium, and additionally, aluminum, zinc, iron and magnanese, among others. Of course, the metal salts include complex salts, i.e. metal chelates, which are well recognized in the tetracycline art. The pharmaceutically unacceptable metal salts embrace most commonly salts of lithium and of alkaline earth metals of atomic number greater than 20, i.e. barium and strontium, which are useful for isolating and purifying the compounds.

It will be obvious that, in addition to their value in therapy, the pharmaceutically acceptable acid and metal salts are also useful in isolation and purification.

The new tricyclic intermediates of the present invention, in addition to their value in synthesis, exhibit valuable antimicrobial activity. They may be employed as bacteriostatic agents, and are further useful in separation and classification of organisms for medical and diagnostic purposes. These new intermediates, by virtue of their B-diketone structure, are also valuable chelating, complexing or sequestering agents, and form particularly stable and soluble complexes with polyvalent cations. They are therefore useful wherever removal of such polyvalent ions is desired, e.g. in biological experimentation and in analytical procedures. Of course, as is well known to those skilled in the art, such fi-diketones may exist in one or more of several tautomeric forms as a result of their ability to enolize. It is fully intended that the {3- diketone structures herein employed embrace such tautomers.

The starting compounds of the present invention are readily preparable by known procedures. Many of these compounds, including both benzoic acid esters and benzophenone starting compounds, have been described in the literature.

The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible within the scope and spirit thereof.

EXAMPLE I Monoethyl ester of 3-(3-methoxybenzyl)adipic acid Method A.Five grams of diethyl 3-(3-methoxybenzoyl)adipate and 2 g. of 5% palladium on carbon in 30 ml. of acetic acid are treated in a conventional Parr shaker at a pressure of 40 p.s.i. of hydrogen gas at 50 C. until 2 moles of hydrogen are taken up. The first mole of gas is taken up rapidly and the second more slowly over a total reaction time of up to about 30 hours. The mixture is filtered, concentrated under reduced pressure to an oil which is vacuum-distilled to obtain the product.

Method B.The 'y-lactone of the enol form of the monoethyl ester of the starting compound is hydrogenated over palladium on carbon by this same method to obtain this product, B.P. 190-1" C. (0.3 mm.). Elemental analysis gives the following results:

Calcd. for (percent): C H O C, 65.29; H, 7.53. Found (percent): C, 65.25; H, 7.68.

The corresponding diethyl ester is prepared by refluxing this product in ethylene dichloride containing ethanol and sulfuric acid. The diester is obtained by diluting the reaction mixture with Water, separating, drying and concentrating the ethylene dichloride layer, and vacuumdistilling the residual oil, n =1.4973. Elemental analysis gives the following results:

Calcd. for (percent): C H O C, 67.06; H, 8.13. Found (percent): C, 67.02; H, 8.31.

The starting compound together with the correspond ing 'y-lactone are prepared by hydrolysis and decarboxylation of diethyl 3-carbo-t.butoxy-3-(3-methoxybenzoyl)adipate (Example XLIII) by refluxing in dry xylene containing p-toluenesulfonic acid. The products are separated by fractional distillation or may be used together as starting compound for this hydrogenation reaction.

EXAMPLE II 3- 3-methoxybenzyl) adipic acid Method A.Amalgamated zinc is prepared by shaking for 5 minutes a mixture of 120 g. of mossy Zinc, 12 g. of mercuric chloride. 200 ml. of Water and 5 ml. of concentrated HCl in a round-bottomed flask. The solution is decanted and the following reagents added: 75 ml. of water and 175 ml. of cone. HCl, 100 ml. of toluene and 52 g. of 3-(3-methoxybenzoyl)adipic acid. The reaction mixture is vigorously boiled under reflux for 24 hours. Three 50 ml. portions of concentrated HCl are added at intervals of 6 hours during reflux.

After cooling to room temperature, the layers are separated, the aqueous layer diluted with 200 ml. of water and extracted with ether. The ether extract is combined With the toluene layer, dried and concentrated under reduced pressure to obtain the product.

Method B.A solution of 6254.4 grams (22.1 mole) 3-(3-methoxybenzoyl)-adipic acid in 38.5 liters of glacial acetic acid is hydrogenated in a 15 gal. stirred autoclave in the presence of 2.5 kg. 5 percent palladium-oncarbon catalyst at 1000 p.s.i.g. and 50 C. until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and the solvent removed from the filtrate by distillation at reduced pressure. This gives 5432 grams of product in the form of an oil. It is further purified by conversion to the dimethyl ester, fractional distillation, and hydrolysis, as follows:

A solution of 5432 grams (20.4 mole) of the crude 3-(3-methoxybenzyl)adipic acid, 3410 grams 106.6 mole) methanol, 10.6 liters ethylenedichloride and 106 ml. concentrated sulfuric acid is stirred and refluxed for 15 hours. The mixture is cooled and Washed with Water (3X5 1.), 5 percent aqueous sodium hydroxide (1X2 1.) and again with water (3X5 1.). The ethylenedichloride solution is dried over 3 lb. anhydrous magnesium sulfate (with 2 lb. Darco G60 activated carbon). The drying agent and carbon are filtered off and the filtrate concentrated at reduced pressure to remove solvent. The residue is distilled through a 3" x 16" vacuum-jacketed fractionating column packed with porcelain saddles. After a forerun of 934.1 grams, the product is collected at 172.0" C./0.2 mm. to 183 C./0.35 mm. This amounts to 3076.6 g. of percent pure ester.

The ester, 2943.4 grams (10.00 mole) is hydrolyzed by heating over a steam bath for 19 hours with 1 kg. (25.0 mole) sodium hydroxide in 6 liters of water. The hydrolysis mixture is acidified to pH ca. 1.0 by addition of concentrated hydrochloric acid and the product is extracted into methylene chloride (1 X4 1. and 2 2 1.). The methylene chloride extract is washed with water (1x4 l.1 8 1.), dried over magnesium sulfate, filtered and freed of solvent by distillation at reduced pressure. This gives 2506 grams of 3-(3-methoxybenzyl)adipic acid in the form of a very sticky oil.

Method C.-A solution of dimethyl 3-(3-methoxybenzyl)adipate (0.01 mole) in 280 ml. of 1:1 tetrahydrofuran: 1,2-dimethoxyethane at a temperature of about 10 C. is treated with a solution of sodium borohydride (0.005 mole) in 30 ml. of 1,2-dimethoxyethane and 10 ml. of water. After 15 minutes, 5 ml. of glacial acetic acid is added and the mixture stirred for 5 minutes. Hydrochloric acid (3 ml. of 6 N) is then added, the mixture stirred for an additional 0.5 hour, then poured into water. The product, 3-[a hydroxy (3 methoxybenzyl)]adipic acid dimethyl ester, is recovered by evaporation.

The hydroxy ester is placed in ml. of anhydrous hydrogen fluoride and allowed to stand overnight. The hydrogen fluoride is then evaporated and the thus produced dimethyl 3-(3-methoxy benzylidene)adipate dissolved in dioxane (300 ml.), treated with 0.3 g. of palladium on charcoal (5%) and subjected to 50 p.s.i. at room temperature until an equimolar proportion of hydrogen is consumed. The mixture is filtered and the filtrate evaporated to dryness under reduced pressure to give the desired compound as the methyl ester. It is hydrolyzed to the acid by the procedure of Method B.

EXAMPLE III Dimethyl 3-( Z-chloro-5-methoxybenzyl) adipate Method A.A mixture of 3.2 g. of dimethyl 3-(3- methoxybenzyl)adipate and 1.4 g. of N-chlorosuccinimide in 30 ml. of trifluoroacetic acid is stirred and heated on a steam bath for 30 minutes. The reaction mixture is then poured into 5% aqueous sodium bicarbonate with stirring, and the mixture extracted with ether. The combined extracts are dried over anhydrous sodium sulfate and then concentrated under reduced pressure to an oil which is vacuum-distilled to obtain the product, B.P. 200 C. (1.1 mm. Hg).

Method B.A mixture of 3.2 g. of dimethyl 3-(3- methoxybenzyl)adipate and 2.1 g. of phosphorus pentachloride in 100 ml. of dry benzene is refluxed for 30 minutes. The reaction mixture is carefully poured into ice water, the benzene layer separated, washed with Water and dried. Concentration of the dried benzene solution under reduced pressure yields an oil which is vaccumdistilled to obtain the product.

Similarly, the diethyl, dibenzyl and dipropyl chloroesters are prepared.

Method C.A solution of 1688 g. of 3-(3-methoxybenzyl)adipic acid and 50 mg. of iodine in 9 liters of glacial acetic acid is stirred while a solution of 450 g. of chlorine in 8 liters of glacial acetic acid is added during about 2 hours. The mixture is kept in the dark during the procedure and the temperature maintained at 10-15 C. The solvent is then removed by concentration under reduced pressure to give 1902 g. of a dark amber oil.

This procedure is repeated with ferric chloride in lieu of iodine with comparable results.

Method D.A mixture of 30.4 g. of diethyl 3-(3-methoxybenzyl)adipate and 12.75 g. of sulfuryl chloride in 250 ml. of benzene is allowed to stand for 3 days at room temperature. At the end of this period, the reaction mixture is concentrated under reduced pressure to a gummy residue which is vaccum-distilled to obtain the product.

Method E.The procedure of Method B is repeated using as starting compound the corresponding dicarboxylic acid to obtain 3 (2 chloro S-methoxybenzyl) adipic acid dichloride.

EXAMPLE IV Diethyl 3-(2-chloro-5-ethoxybenzyl) adipate This product is obtained by the procedure of Method A of Example III employing diethyl 3-(3-ethoxybenzyl) adipate in lieu of dimethyl 3-(3-methoxybenzyl)adipate.

EXAMPLE V 2-(Z-carbethoxyethyl)-5-methoxy-8-chloro-4-tetralone Method A.A mixture of 2 g. of diethyl-3-(2-chloro-5- methoxybenzy1)adipate (Example III) and 30 g. of polyphosphoric acid is heated on a steam bath for 30 minutes and then poured into ice water. The oil then separates and is collected.

Method B.A mixture of 2.0 g. of the di-acid chloride of 3-(2-chloro-5-methoxybenzyl)adipic acid in 30 ml. of carbon disulfide is cooled to C. and 4 g. of aluminum chloride added portionwise to the cooled mixture. The mixture is stirred for 30 minutes and then allowed to warm to room temperature where a vigorous reaction ensures. After the vigorous reaction subsides the mixture is warmed on a steam bath, cooled, diluted with water and the carbon disulfide steam distilled. The mixture is extracted with chloroform and the product obtained by drying and concentrating the chloroform extract. The product is the free acid which, if desired, is converted to the desired lower alkyl ester by conventional methods. For example, the methyl ester is prepared as follows:

A mixture of 2002 g. (7.1 moles) of the tetralone acid, 3.1 chloroform, 682 g. (21.3 mole) methanol and 21.2 ml. conc. sulfuric acid is refluxed with stirring on a steam bath for 20 hours. The reaction mixture is then chilled and 2 1. each of chloroform and water are added. The organic phase is separated and washed successively with two 2 1. water, one 1 l. 2% aqueous sodium hydroxide and three 4 1. water to a final pH of about 7.5. After drying over anhydrous sodium sulfate and treatment with Darco KB activated carbon the solution is filtered and concentrated to a dark oil at reduced pressure. The oil is taken up in 6.1. hot ethyl acetate and 11 l. hexane added. The solution is chilled to -5 C. with stirring and 1404 g. 2 (2 carbomethoxyethyl) 5 methoxy-8- chloro-4-tetralone recovered by filtration, hexane-washing and air-drying. The product melts at 101.0l02.4 C.

EXAMPLE v1 Z-(Z-carboxyethyl)-5-methoxy-8-chloro-4-tetralone A polyethylene container is charged with 1809 g. (6.0-3 mole) 3 (2 chloro 5-methoxybenzyl)adipic acid and chilled in an ice bath while 7 kg. liquid hydrogen fluoride is introduced from an inverted, chilled tank. The mixture is swirled to make homogeneous and then left to evaporate partially overnight in a hood. Most of the hydrogen fluoride that remains is removed by placing the polyethylene container in Warm water to cause rapid evaporation. The remainder is removed by quenching in about 10 l. Water. The product is then extracted into chloroform, washed with water and dried over magnesium sulfate. Removal of the drying agent by filtration and the solvent by distillation gives a gum that is triturated with ether and filtered. This gives 1031 g. of crude product that is recrystallized from a mixture of 16 1. ethanol, 2 l. acetone and 1 l. ethylene dichloride, with activated carbon treatment. The first two crops amount to 863.9 grams, of white crystalline product melting at 175.0- 180.5 C.

Elemental analysis gives the following results:

Calcd. for C H O Cl (percent): C, 59.47; H, 5.35; Cl, 12.54. Found (percent): C, 59.51; H, 5.42; Cl, 12.60.

Ultraviolet absorption shows max at 223 mp.

255 m (e=7,900) and 326 m (e=4,510). Infrared absorption maxima appear at 5.76 and 5.99p..

This product is also obtained by hydrolysis of the product of Method A, Example V, by treatment with HCl in acetic acid.

The methyl ester, ethyl ester (M.P. 5759 C.) and benzyl ester (M.P. 8485 C.) are prepared by conventional methods.

3-(3-methoxybenzy1)adipic acid, treated with HF as described, yields 2-(2-carboxyethyl)-7-methoxy-4-tetralone, which melts at 15 8-9 C. after two recrystallizations from benzene-hexane and exhibits ultravolet absorption maxima at 225 m (e=13,500) and 276 m (e=16,000) in methanolic HCl and NaOH.

Analysis.Calcd. for C 4H O (percent): C, 67.73; H, 6.50. Found (percent): C, 67.67; H, 6.48.

EXAMPLE VII 2- 2-carboxyethyl) -6-ch10ro-7-methoxy-4-tetralone This substance is a byproduct of the cyclization of the products of Example III. It is separated from the crude '2-(Z-cafiboxyethyl)-5-methoxy-8-chloro 4 tetralone of Example VI by virtue of its chloroform insclubility. 2900 g. of the crude tetralone are leached six times with 8 liters portions of hot chloroform. 170 g. of White solid remains, melting at 236-239 C. The methyl ester is prepared by the procedure of Example V, Method B.

EXAMPLE VIII 2- (Z-carbomethoxyethyl) -5-benzyloxy-8-chloro- 4-tetralone 2 (Z-carboxyethyl)-5-methoxy-8 chloro-4-tetralone (25 g.), glacial acetic acid (200 ml.) and 48% hydrobromic acid (50 ml.) are heated at under nitrogen for twenty-four hours. The cooled solution deposits a crystalline solid. The mixture is poured over two parts ice and the total solid crop isolated by filtration and thoroughly washed with water. The crude 2-(2-carboxyethyl)-5-hydroxy-8-chloro-4-tetralone obtained in this way is recrystallized from acetonitn'le to obtain 18.8 g. melting at 1648 C.

Elemental analysis, Calcd. for C H ClO (percent): C, 58.11; H, 4.88; Cl, 13.20. Found (percent): C, 57.99; H, 4.87; CI, 12.73.

14.5 g. of this product is placed in 200 m1. dry methanol and the mixture refluxed for 30 minutes as anhydrous HCl is passed through. The now clear yellow solution is allowed to stand overnight, and the methanol is then re moved in vacuo. The residual gum is extracted exhaustively with hexane and the combined extracts are concentrated and cooled. 11.8 g. of the white, crystalline methyl ester separates and is filtered off and recrystallized from hexane. The ester melts at 6869.5 C. and analyzes as follows: calcd. for C H ClO (percent): C, 59.45; H, 5.35; Cl, 12.6. Found (percent): C, 59.16; H, 5.38; Cl, 12.6.

5.6 g. (0.02 mole) of this substance is dissolved in 500 ml. anhydrous methanol and to this is added 0.02 mole sodium methoxide and 500 ml. benzene. The mixture is concentrated to dryness in vacuo at room temperature, then heated at 100 C. and 0.1 mm. for 10 minutes. The residue is maintained under high vacuum at room temperature for 16 hours, and the dry solid added to 50 m1. benzyl bromide together with suflicient dimethyl formamide to solubilize. The mixture is heated at 100 C. for 48 hours with stirring, then cooled and filtered. The filtrate is concentrated at reduced pressure and the residual oil chromatographed on acetone-washed and dried silicic acid in chloroform. The first effiuent fraction consists of unchanged starting material. The main fraction, recognized by a negative ferric chloride test, deposits crystalline 2 (2-carbomethoxyethyl)-5-benzyloxy-8-chloro-4 tetralone on standing.

EXAMPLE IX 2-carbomethoxy-S-methoxy-S-chloro-3 ,4,10-trioxo- 1,2,3,4,4a,9,9a,10-octahydroanthracene 30 grams of 2-(2-carbomethoxyethyl)-5-methoxy-8- chloro-4-tetralone (0.1 mole), prepared as described in Example V, Method B, is dissolved together with 24 grams dimethyloxalate (0.2 mole) by warming with 135 ml. freshly distilled dimethyl formamide in a well dried two liter flask which has been flushed with dry nitrogen. The solution is cooled to 20 C. and to it is added all at one time 0.4 mole sodium hydride in the form of a 50% oil dispersion which has been exposed to the atmosphere for 24 hours in order to produce a deactivating coating. The reaction mixture is maintained at 2025 C. with an ice bath. 0.1 mole dry methanol is now added, and the temperature rises spontaneously to 4050 C. When the temperature begins to fall (about 5 minutes after addition of the methanol) the reaction vessel is removed from the ice bath and quickly placed in an oil bath at 110 C. The reaction temperature is brought with dispatch to 90 C. and maintained there for minutes or until active bubbling ceases if this occurs sooner.

The flask is now immediately transferred 'back to the ice bath, and when the temperature reaches C., 100 ml. of glacial acetic acid is added at such a rate that the temperature does not exceed 30 C. At this point, a golden yellow precipitate appears. 150 ml. methanol and 50 ml. water are added and the mixture is digested at 45 C. for 15 minutes and then stirred in an ice bath for an hour. If only a scanty crop of crystals is present at this time the mixture may be stored in the refrigerator overnight before proceeding. It is now transferred to a separatory funnel to permit separation of the oil from the sodium hydride oil dispersion. The suspension is then filtered with suction and the filter cake triturated three times with 100 ml. portions of hot hexane to extract impurities. The washed solid is next stirred with 200 ml. water, filtered, and then digested with 500 ml. refluxing methanol for minutes, to effect further purification. 1516 grams of bright yellow needles are obtained. The product melts at ZOO-205 C. and exhibits no carbonyl absorption below 6a. In 0.01 N methanolic HCl it exhibits ultraviolet absorption maxima at 406 mu (6: 14,200) and at 275-290 mu (e=5,940). In 0.01 N methanolic NaOH it exhibits maxima at 423 mu (6 13,950) and at 340 my (6:7,120).

24 EXAMPLE X 2-carbomethoxy-6-chloro-7'methoxy-3,4,1-0-trioxo- 1,2,3,4,4a,9,9a,10-octahydroanthracene 2 (Z-carbomethoxyethyl)-6-chloro-7-methoxy-4-tetralone, prepared in Example VII, 30 g., is dissolved in 24 g. dimethyl oxalate in 300 ml. dry distilled dimethyl formamide by warming. The solution is then cooled under nitrogen in an ice-salt bath and 19.86 g. sodium hydride (51.2% in oil) added all at once as the temperature is maintained below 20 C. The ice bath is removed and the temperature rises spontaneously to 30 C., whereupon the bath is replaced briefly to control the vigorous reaction. The reaction mixture is then heated to 80 C. for 58 minutes, cooled to below 0 C., and treated with 100 ml. acetic acid, added at such rate that the temperature does not reach 25 C. The reaction mixture is now poured into four volumes of chloroform. The chloroform solution is washed with water, then with saturated brine, and dried over anyhdrous sodium sulfate. The solvent is removed in vacuo, and the residue is treated with 350 ml. methanol. After standing for several hours at room temperature the slurry is filtered to obtain 12.5 g. yellow crystalline product, melting at 228-231 C. with decomposition and gas evolution. Recrystallization from chloroform-methanol raises the melting point to 235.6236.8 C.

Analysis.-Calcd. for (percent): C H Cl C, 58.21; H, 4.31; Cl, 10.11. Found (percent): C, 58.53; H, 4.43; Cl, 10.10.

EXAMPLE XI 2-carbobenzyloxy-5 -methoxy-8 -chloro-3 ,4, 1 O-trioxo- 1,2,3,4,4a,9,9a,l0-octahydroanthracene 2 (2 carboxyethyl)-5-methoxy-8-chloro-4-tetralone, 0.02 mole, is combined with 500 ml. anhydrous methanol and to this is added 0.02 mole sodium methoxide and 500 ml. benzene. The mixture is concentrated to dryness in vacuo at room temperature, then heated at 100 C. and 0.1 mm. for 10 minutes. The residue is maintained under high vacuum at room temperature for 16 hours, and the dry solid added to 50 ml. benzyl bromide together with sufficient dimethyl formamide to solubilize. The mixture is heated at 100 C. for 48 hours with stirring, then cooled and filtered. The filtrate is concentrated under reduced pressure to obtain the benzyl ester as residue. Purification is effected by washing of a chloroform solution with aqueous sodium bicarbonate.

This substance is dissolved together with 0.04 mole dibenzyl oxalate in 50 ml. dry, distilled dimethyl formamide. To this is added 0.08 mole sodium hydride in the form of a 50% oil dispersion, while maintaining the temperature at about 20-25 C. Benzyl alcohol, 0.02 mole, is added, and the mixture is heated to C. for 5 minutes, then cooled to 20 C. and slowly acidified with glacial acetic acid. The reaction mixture is next evaporated to dryness under reduced pressure and the residue is taken up in chloroform. The chloroform solution is washed with water, then with brine, dried over sodium sulfate, treated with activated carbon and filtered. The filtrate is evaporated at reduced pressure to obtain the product as residue. It is purified by evaporation of the highly fluorescent, less polar eluate fraction from silicic acid chromatography in chloroform.

EXAMPLE XII 2-carbomethoxy-S-methoxy-8-chloro-3 ,4,10-trioxo- 1,2,3,4,4a,9,9a, 1 O-octahydroanthracene Clean sodium metal (3.68 g.) is dissolved in methanol (50 ml.) and the solution evaporated to a dry white solid in vacuo (this is most successfully carried out by using rotary vacuum equipment). Dimethyloxalate (9.44 g.) and benzene ml.) are then added to the flask and refluxing is carried out for about 10 minutes under nitrogen (not all of the solids dissolve but the cake is broken up). The solution is cooled and dimethylformamide (50 ml.) then added followed by the dropwise addition of a solution of 2 (2 carboxyethyl) -methoxy-8-chloro-4- tetralone (Example VI) (11.3 g.) in dimethylformamide (100 ml.) during one hour at 20 under N with stirring, and stirring at room temperature under N is continued overnight. The solution is then poured into cold water (1 l.) and extracted twice with chloroform. The chloroform extract is discarded and the aqueous solution acidified with HCl solution. The product is obtained by extraction with chloroform (3x200 rnl.), backwashing once with water, drying over anhydrous Na SO treat ment with charcoal, filtration and evaporation of the solvent in vacuo to give a red gum (16.4 g.) with is 2-(2- carb oxyethyl) 3-methyloxalyl-5 methoxy-9-chloro-4-tetralone.

U.V. absorption maxima in 0.01 N NaOH at 258 and 363 m maximum in 0.01 N HCl at 347 m minimum at 277 m The gum gives a deep red color with ferric chloride in methanol and liberates CO from a saturated NaHCO solution.

The acid is esterified by dissolving in chloroform (1 1.), methanol (50 ml.) and cone. H 50 (10 ml.) and refluxing gently for hours. The solution is cooled, poured into excess water and the chloroform layer separated. The aqueous layer is extracted with chloroform (250 m1.) and the combined chloroform extracts are backwashed twice with cold water. The extract is then dried over anhydrous sodium sulphate, treated with activated charcoal, filtered and evaporated to a red gum in vacuo. This gum does not liberate CO from saturated bicarbonate solution, and gives a deep red color with ferric chloride in methanol.

The ester product, 3.825 grams, and 1.275 g. of sodium hydride (56.5% solution in oil) are dissolved in 25 ml. of dimethylformamide. An exothermic reaction sets in with the evolution of hydrogen gas. After the evolution of gas ceases the mixture is warmed at 40 C. for /2 hour where further evolution of hydrogen gas occurs and the reaction mixture darkens. The reaction mixture is finally digested on a steam bath for 10 minutes after which it is cooled and acidified with glacial acetic acid (15 ml.). The product is then obtained by dilution of the mixture with water followed by extraction with chloroform. The dried chloroform solution is concentrated under reduced pressure to obtain a gummy residue which crystallizes on trituration in methanol. The orange-yellow crystalline product, 2-carbomethoxy-5-methoxy-8-chloro-3,4,10-trioxo-1, 2,3,4,4a,9,9a,10-octahydroanthracene, (1.2 g.) melts at 196201.5 C.

EXAMPLE XIII 2-carb omethoxy-S-hydroxy-Schloro-3 ,4, l O-trioxo- 1,2, 3 4,4a,9,9a,10-octahydroanthracene Dimethyl oxalate, 0.84 g., and 2-(2-carbomethoxyethyl)-S-hydroxy-8-chloro-4-tetralone, 2.0 g., are added to a suspension of 0.34 g. sodium hydride in 10 ml. dimethyl formamide and the mixture is heated to 70 C. for three minutes. After cooling, the reaction mixture is treated with 10 ml. acetic acid and evaporated to dryness at reduced pressure. The residual gum is triturated with water to remove sodium acetate and chromatographed on silicic acid in chloroform. The main efiluent fraction is dried on a 'bright yellow solid which is crystallized from chloroform-hexane to provide 380 mg. product melting at 218- 219.5 C.

Elemental analysis-Calculated for C H O Cl (percent: C, 56.7; H, 3.9; Cl, 10.5. Found (percent): C, 56.86; H, 3.89; Cl, 10.8.

EXAMPLE XIV Diethyl 3-(a-hydrox'y-3 methoxybenzyl) adipate This product is obtained by treating 5 g. diethyl 3-(3- methoxybenzoyl) adipate and 2 g. 5% palladium on carbon in ethanol with 40 p.s.i. hydrogen gas at room temperature until one molar equivalent of hydrogen is consumed. The reaction mixture is filtered and concentrated at reduced pressure to obtain the product.

Itis further converted to diethyl 3-(a-N,N-dimethylamino-3-methoxybenzyl) adipate in the following manner:

The a-hydroxy benzyl adipate ester, 0.01 mole in 15 m1. dimethoxyethane, is added to a stirred mixture of 1.9 g. (0.01 mole) p-toluenesulfonyl chloride and 2.5 ml. dry pyridine in an ice bath. When the reaction subsides the mixture is permitted to warm to room temperature, stirred for three hours, and poured into 50 ml. water. The pH is adjusted to 5 and the resulting tosyl ester recovered by filtration.

The tosylate (0.0025 mole) is combined with 25 ml. dimethoxyethane and added dropwise to a stirred solution of 0.015 mole dimethylamine in 50 ml. dimethoxyethane at 0 C. After addition is complete, stirring is continued for an hour at 0 and the reaction mixture is then heated at 60 for three hours under a Dry Ice condenser. The mixture is next evaporated in vacuo and the residue Washed with water to remove dimethylammonium toluenesulfonate. The product is recovered by filtration from the water. Substitution of monomethylamine for dimethylamine in this procedure provides the corresponding oc-N- methylamino derivative.

EXAMPLE XV 2- Z-carbomethoxyethyl) -5-rnethoxy-4-tetralone 2 (2 carbomethoxyethyl) 5 methoxy 8 chloro- 4-tetralone (1.5 g.) is combined with 5% palladium-oncharcoal (0.37 g.), triethylamine (0.5 g.) and methanol 270 ml. in a standard Parr hydrogenation bottle and subjected to 50 pounds of hydrogen pressure. The absorption of hydrogen levels off at approximately one molar equivalent. The catalyst is filtered off, the solution taken to dryness, and triethylamine hydrochloride is removed by washing with water. The residual white solids weigh 1.1 g. and melt at 6366 C. After two recrystallizations frsom hexane and one from ether the product melts at 8 87.

Analysis.-Calcd. for C H 0 (percent): C, 68.68; H, 6.92. Found (percent): C, 68.59; H, 6.98.

EXAMPLE XVI 2- (Z-carboxyethyl) 7-hydroxy-4-tetralone 3-(3-methoxybenzyl) adipic acid, 22.46 g., is heated at reflux with hydriodic acid (specific gravity 1.5) for 3 hours and the methyl iodide formed is separated. The solution is evaporated in vacuo and the resulting gum triturated with cold Water to yield 14.7 g. of yellow crystalline product. Dried and recrystallized from aqueous acetone the product is obtained in the form of white crystals melting at 183.5185.5 C.

Elemental analysis.Calculated for C H O (pergegt): C, 66.65; H, 6.02. Found (percent): C, 66.60; H,

The same product is obtained by refluxing a mixture of 0.5 g. of the 3-(3-methoxybenzyl)adipic acid with 25 ml. 48% HBr for 18 hours, then pouring the reaction mixture into 3 volumes of water, and filtering the resulting 0.4 g. of crystalline precipitate.

EXAMPLE XVII 2-( Z-carbomethoxyethyl) 5-methoxy-8-nitro-4-tetralone 'One gram of the Example XV product is slowly added to 10 ml. of concentrated sulfuric acid containing 2 ml. of 70% nitric acid at a temperature of 05 C. The solution is stirred for 15 minutes and allowed to warm to room temperature. The mixture is poured into ice-water mixture and extracted with chloroform, the chloroform layer separated, dried and concentrated to obtain the product.

2? EXAMPLE XVIII 2-(2-carboxyethyl-S-hydroxy-8-amino-4-tetralone One molecular proportion of aniline is dissolved in 2 N HCl, employing about 20 ml. thereof per gram of aniline, and the solution treated with one molecular proportion of NaNO at to 10 C. The benzenediazonium chloride solution is then mixed with stirring at 0 to 20 C. With an aqueous solution of 2-(2-carboxyethyl)-5-hydroxy-4- tetralone sodium salt and sufficient sodium carbonate to neutralize the excess HCl in the diazotised aniline solution. The pH of the solution is in the range 8-10. Stirring is continued at 0 C. for approximately two hours after which careful neutralization of the reaction mixture yields the S-phenylazo compound. The product is collected on a filter, washed and dried.

One part by weight of 2-(2-carboxyethyl)-5-hydroxy-8- phenylazo-4-tetralone is mixed with 20 parts by weight of methanol and /5 part by weight of 5% palladium-oncarbon catalyst is added to the mixture which is then hydrogenated at 30-45 p.s.i. of hydrogen gas in a conventional shaker apparatus at 30 C. until two molar equivalents of hydrogen are taken up.

After filtration, the product is recovered by high vacuum distillation of the residue obtained by removal of the solvent in vacuo. Care must be exercised to protect the amino phenol from air. It can be stabilized byacetylation, as follows:

The crude amine is placed in 20 parts water containing one molar equivalent of HCl, and 2.2 molar equivalents of acetic anhydride are added. Sufficient sodium acetate is then added to neutralize the HCl and the solution is warmed to 50 C. After 5 minutes the mixture is cooled and the crude acetate separated by filtration. The solid is then dissolved in cold 5% sodium carbonate solution and reprecipitated with 5% HCl. The 2-(2-carboxyethyl)-5-hydroxy-8-N-acetylamino-4-tetralone obtained in this manner is a preferred form of the amino compound for further reaction sequences.

EXAMPLE XIX 3-(Z-amino-S-hydroxybenzyl) adipic acid The procedure of Example XVIII is repeated using 3- (3-hydroxybenzyl)adipic acid as starting compound to obtain this product. It may be converted to the product of Example XVIII by the ring closure procedure of Example VI.

EXAMPLE XX 3- (2-chloro-5-hydroxybenzyl) adipic acid Three parts by weight of the product of Example XIX (obtained by evaporating the methanol) is protected from air, immediately mixed with parts by weight of 10% aqueous hydrochloric acid at 0 C., and diazotized by gradual addition of aqueous sodium nitrile solution. Addition of sodium nitrite is continued until a positive starch iodide test on a few drops of the reaction mixture is obtained in the conventional fashion. The resulting solution is then added to 15 parts of a boiling 10% solution of cuprous chloride in aqueous hydrochloric acid. The mixture is boiled for 10 minutes and allowed to cool. The product separates from the cooled mixture and is collected in the conventional manner.

This procedure is used for the preparation of 3-(2- substituted-5-hydroxy-benzyl) adipic acid compounds such as 2-bromo (using Cu Br and HBr), 2-iodo (using KI and H 80 EXAMPLE XXI 3- ix-hydroxya- 2-chloro-5-methoxy-phenyl ethyl] adipic acid diethyl ester To a solution of 3-(2-chloro-5-methoxybenzoyl)adipic acid diethyl ester in dimethoxyethane is added dimethoxyethane solution containing a molar equivalent of methyl 28 magnesium bromide. After standing for 30 minutes, the reaction mixture is acidified cautiously with ice and aqueous 6 N HCl, and extracted with methylene chloride.

The extracts are combined, washed with water, dilute aqueous sodium bicarbonate and water, dried and concentrated under reduced pressure to obtain the product.

EXAMPLE XXII 3-[ot-(2-chloro-5-methoxyphenyl)ethyl] adipic acid diethyl ester The product of Example XXI, 2 g., is dissolved in 150 ml. of glacial acetic acid and hydrogenated at a pressure of 40 p.s.i. of hydrogen gas for 24 hours at room temperature in the presence of 2 g. of 5% palladium-in-car-bon catalyst. The mixture is filtered and then concentrated. The product is obtained by vacuum distillation of the residue.

EXAMPLE XXIII 3,3 ,4-trimethoxybenzophenone A mixture of 40 g. of 3-methoxybenzoyl chloride, 32 g. of veratrole and 250 ml. of carbon disulfide in a 3 neck rouncl bottom flask fitted with reflux and stirrer is cooled to 0 C. Then 40 g. of alaminum chloride is added portionwise to the cooled mixture and the mixture stirred for 45 minutes, after which it is allowed to warm to room temperature. A vigorous reaction ensues with the separation of a yellow precipitate. The mixture is carefully warmed on a steam bath and stirred for 1 /2 hours. Water is then added to the cooled mixture and the carbon disulfide is steam distilled off. The resultant mixture is then extracted with chloroform and the chloroform layer separated, washed with dilute hydrochloric acid, followed by dilute sodium hydroxide and then dried and concentrated under reduced pressure. The residual oil is distilled to obtain the product, B.P. 216-2l8 C. at 1.5 mm. mercury. A 65% yield of product is obtained. The viscosity product is stirred in absolute methanol and crystallizes, M.P. 86 C.

EXAMPLE XXIV 3 ,3 ,4-trimethoxydiphenylmethane Method A.-A solution of 5 g. of 3,3',4-trimethoxybenzophenone in 200 ml. of ethanol containing 1 g. of copper chromium oxide is hydrogenated at 180 C. and atmospheres of hydrogen gas for 1.5 hours. The resultant solution is filtered and concentrated under reduced pressure. The residual oil is distilled to obtain the product B.P. 192194 C. at 2.5 mm. mercury. The product crystallizes on standing, the melting point of the crystals being 4546 C. Elemental analysis gives the following results:

Calcd. for C H O (percent): C, 74.39; H, 7.02. Found (percent): C, 74.50; H, 7.18.

Method B.This product is also obtained by hydrogenation of the starting compound of Method A using 10% palladium on carbon in ethanol at 50 C. and 40 p.s.i. of hydrogen gas. The hydrogenation procedure is also carried out at room temperature, although the uptake of hydrogen is considerably slower than at 50 C. The product is obtained by filtration and concentration of the hydrogenation mixture.

EXAMPLE XXV 3 ,3 ',4-trihydroxydiphenylmethane Two grams of 3,3,4-trimethoxydiphenylmethane are dissolved in 10 ml. of acetic acid and 10 ml. of 48% hydrobromic acid and the mixture refluxed for 5 hours. The reaction mixture is concentrated under reduced pressure to obtain a residual gum which is vacuum-distilled (B.P. 230 C. at 0.5 mm. of mercury). The distillate, a colorless gum, crystallizes. A 62% yield of product is obtained, M.P. 103.5104 C.

29 EXAMPLE XXVI 3- (3-hydroxybenzyl) -hexa-a-2,4-di-enedioic acid A mixture of 3.5 g. of 3,3,4-trihydroxydiphenylmethane in 50 ml. of acetone and 50 ml. of 10% aqueous sodium hydroxide is cooled to C. Thirty ml. of 35% aqueous hydrogen peroxide solution is then added dropwise, the mixture turning pale pink after to minutes. An exothermic reaction occurs with considerable boiling and foaming. The mixture is allowed to stand for 1 hour and is then extracted with ethyl acetate, the extract being discarded. The aqueous solution is then acidified and extracted with ethyl acetate. Concentration of the ethanol acetate extract after drying gives the product as a gummy residue.

EXAMPLE XXVII 3- (3-hydroxybenzyl) adipic acid The product of the preceding example (105 mg.) is dissolved in 13 ml. of ethanol containing 1 drop of concentrated hydrochloric acid and hydrogenated over platinum oxide at 1 atmosphere of hydrogen gas at room temperature. The hydrogen uptake is exactly 2 molecular equivalents. Filtration and concentration of reaction mixture gives the product.

EXAMPLE XXVIII 3-(3-methoxybenzyl)adipic acid dimethyl ester The acid product of the preceding example is dissolved in aqueous sodium hydroxide (4 molar equivalents) and agitated with 3 molar equivalents of dimethyl sulfate at 40 C. for 6 hours. The resultant solution is then diluted with water and extracted with chloroform. The chloroform layer is separated, dried and concentrated under reduced pressure to yield an oil, B.P. 205 to 210 C. at 0.2 mm. mercury. This product is also obtained by treatment of the starting compound with diazomethane in diethyl ether.

In a similar manner the corresponding ethyl and propyl esters are prepared.

EXAMPLE XXIX 3 3-methoxyb enzyl) hexa-2,4-dienedioic acid Five grams of 3,34-trimethoxydiphenylmethane are dissolved in 50 m1. of acetic acid containing about 10 drops of water and ozonized air containing about 40% O is then passed into the mixture for 1.5 hours (total of about 6 moles of ozone). The resultant yellow solution is poured into 1 liter of water and extracted with chloroform. The chloroform layer is separated, washed with aqueous sodium bicarbonate solution and concentrated under reduced pressure. The residue is dissolved in ethanol containing 2 g. of KOH and the mixture allowed to stand at room temperature for 2 days after which it is diluted with water and extracted with chloroform. After separation of the chloroform layer the aqueous alkaline solution is acidified with dilute hydrochloric acid and extracted with chloroform. Concentration of the chloroform extract gives the acid product.

The methyl, ethyl and propyl diesters of this acid are prepared by refluxing the acid for 3 days in ethylene dichloride containing the appropriate alcohol and sulfuric acid.

EXAMPLE XXX 3-(3-methoxybenzyl)adipic acid dimethyl ester The ester of the preceding example is hydrogenated in ethanol over 10% palladium on carbon at 1 atmosphere of hydrogen gas at room temperature. The theoretical uptake of hydrogen gas (2 molar equivalents) is very rapid. The product is obtained by filtration and concentration of the hydrogenation mixture.

In similar fashion the corresponding free acid is obtained by hydrogenation of the free acid of the preceding example.

3O EXAMPLE XXXI The following monoester compounds are prepared by reduction of corresponding benzoyl diesters according to the methods of Example I. The free adipic acid derivatives are prepared by the methods of Example H from the corresponding benzoyl adipic acids. The products are subsequently converted to the corresponding diesters by conventional procedures, e.g., Example II, Method B.

3-benzyladipic acid monoethyl ester 3-(2-ethyl-5-hydroxybenzyl) adipic acid monoethyl ester 3-(2-chloro-5-methoxybenzyl)adipic acid monomethyl ester 3-(Z-dimethylamino-S-methoxybenzyl)adipic acid monomethyl ester 3-(2-amino-5-methoxybenzyl) adipic acid 3-(Z-acetamido-S-methoxybenzyl) adipic acid 3- 3-hydroxy-benzyl) adipic acid monoethyl ester 3-(3-methy1-5-hydroxybenzyl)adipic acid monoethyl ester 3-(2,3dimethyl-5-hydroxybenzyl)adipic acid monoethyl ester 3-(2-methyl-5-hydroxybenzyl)adipic acid monoethyl ester 3-(3-dimethylamino-S-hydroxybenzyl)adipic acid monoethyl ester 3-(2,3-dimethylbenzyl)adipic acid monoethyl ester 3-(3,5-dimethoxybenzyl) adipic acid monoethyl ester 3-(3-hydroxybenzyl)adipic acid monoethyl ester 3-(3-isopropyl-5-hydroxybenzyl)adipic acid monoethyl ester 3-(2,3-diethyl-5-hydroxybenzyl)adipic acid monoethyl ester 3-(5-benzyloxybenzyl)adipic acid monoethyl ester 3-(2-ch1oro-5=benzyloxybenzyl)adipic acid monoethyl ester 3-(3-propionyloxybenzyl)adipic acid monoethyl ester 3-(3-acetyloxybenzyl)adipic acid monoethyl ester 3-(2-amino-5-benzyloxybenzyl)adipic acid monobenzyl ester 3-(2-propyl-5-propoxybenzyl)adipic acid monomethyl ester 3 (2-meth0xy-3,S-ditrifluoromethylbenzyl) adipic acid monomethyl ester 3- (2-trifluoromethyl-3,S-dibutoxybenzyl) adipic acid monoethyl ester 3 (2-trifluoromethyl-3-ethylamino-5 -methoxyb enzyl) adipic acid monoethyl ester 3-(3-butyrylamidobenzyl)adipic acid monoethyl ester 3- (Z-trifiuoromethyl-5-hydroxybenzyl) adipic acid monobenzyl ester 3-(2-chloro-5-hydroxybenzyl)adipic acid monobenzyl ester 3-(2-chloro-3-methyl-5-hydroxybenzyl)adipic acid monoethyl ester 3-(2-chloro-3-isopropyl-S-hydroxybenzyl) adipic acid monoethyl ester 3-(2-chl0ro-3-amino-5-methoxybenzyl)adipic acid monoethyl ester 3-(2-chloro-3-methyl-5-methoxybenzyl)adipic acid monobenzyl ester 3- (2-chloro-3-ethyl-5-methoxybenzyl)adipic acid monobenzyl ester 3- (Z-rahloro-3-dimethylamino-5-hydroxybenzyl) adipic aci 3-(3,5-dimethoxybenzyl)adipic acid monoethyl ester 3-(Z-methylamino-S-propoxybenzyl)adipic acid monoethyl ester 3-(Z-methyl-S-hydroxybenzyl) adipic acid 3-(2-amino-5-benzyloxybenzy1)adipic acid monomethyl ester 3-(3-acetamido-5-hydroxybenzyl)adipic acid monoethyl ester 3-(2-chloro-3,S-dihydroxybenzyl)adipic acid monoethyl ester 3-(3-trifluoromethyl-5-hydroxybenzyl)adipic acid monoethyl ester 3-(3-hydroxybenzyl)adipic acid monoethyl ester.

The corresponding diesters are prepared by esterification of these compounds with the selected alcohol by the usual method.

Those compounds having a benzyloxy substituent are reduced by the procedures of Methods A or C of Example II. Of course, the procedure of Example II, Method A, results in hydrolysis of the ester groups and necessitates re-esterification.

EXAMPLE XXXII avoided by employing the corresponding methyl ethers;

likewise, amino substituents are employed in acetylated form.

The a-amino benzyl adipates obtained in this manner are further converted to the corresponding 1-amino-4- tetralones of structure III by the procedure of Example EXAMPLE XXXIII The procedure of Example XXI is repeated to produce the following compounds from corresponding benzoyladipic acid compounds using lower alkylmagnesium halides.

diethyl 3- u-hydroxy-a-phenethyl) adip ate diethyl 3- a-hydroxy-o- (2-ethyl-5-hydroxyphenyl) ethyl] adipate dimethyl 3- [oz-hYdIOXY-a- (Z-dimethylamino-S-methoxyphenyl) ethyl] adipate dimethyl 3- a-hydroxy-a- Z-amino-S-methoxyphenyl) ethyl] adipate dimethyl 3- a-hydroxy-a- Z-acetamido-5-methoxyphenyl) ethyl] adipate diethyl 3- [a-hydroxy-u- 3 -hydroxyphenyl ethyl] adipate diethyl 3 a-hydroxy-a- (2-chloro-5-methoxyphenyl) ethyl] adipate diethyl 3- a-hydroxy-ix- 3-methyl-5-hydroxyphenyl) ethyl] adipate diethyl 3- [a-hydIOXY-a- 3,5 -dimethoxypheny1) ethyl] adipate diethyl 3- oc-hYdI'OXY-oc- 3 -methoxyphenyl propyl] adip ate diethyl 3- [u-hydroxy-ix-(Z-chloro-S-methoxyphenyl propyl] adipate diethyl 3- [.a-hydroxy-u- (2-chl0ro-5-methoxyphenyl) butyl] adipate diethyl 3- a-hydroxy-u- 3-methoxyphenyl ethyl] adip ate.

In the case of the precursors to the compounds listed above which possess an active hydrogen, 2.5 moles of Grignard reagent are employed.

The compounds containing an amino-substituent are isolated from the reaction mixture by the substitution of saturated aqueous ammonium chloride for 6 N HCl.

EXAMPLE XXXIV The a-hydroxy group of Example XXXIII compounds is hydrogenolyzed according to the method of Example XXII to afford the following compounds:

diethyl 3- u-phenethyl) adipate diethyl 3- [oc- (Z-ethyl-S-hydroxyphenyl ethyl] adipate dimethyl 3 a- 2-chloro-5-methoxyphenyl) ethyl] adip ate dimethyl 3- u- (2-dimethylamino-S-methoxyphenyl) ethyl] adipate dimethyl 3- a- (Z-amino-S-methoxyphenyl ethyl] adipate dimethyl 3- [oc- (2-acetamido-5-methoxyphenyl propyl] adipate diethyl 3 a- (3 -hydroxyphenyl ethyl] adipate 32 diethyl 3- [oc- 3-methyl-5-hydroxyphenyl ethyl] adipate diethyl 3- a-( 3 ,5 -dimethoxyphenyl) ethyl] adipate diethyl 3- [a- (3 -methoxyphenyl propyl] adipate diethyl 3- oa- 2-chloro-5-methoxyphenyl propyl] adipate diethyl 3- [0L- 2-chloro-5-methoxyphenyl butyl] adipate diethyl 3- [oc- S-methoxyphenyl) ethyl] adipate.

EXAMPLE XXXV The following compounds are prepared according to the methods of Example VI by ring closure of corresponding compounds.

2- Z-carbethoxyethyl) -4-tetralone 2- 2-cyanoethyl -5-methoxy-8-ethyl-4-tetraloue Z-(Z-carboxyethyl) -5-methoxy-8-dimethylamino-4 tetralone 2 (Z-carbobenzyloxyethyl -5-methoxy-8-amino-4- tetralone 2- (2-carbopropoxyethyl -5-methoxy-8-acetamido 4- tetralone 2- 2-carbob enzyloxyethyl) -5-hydroxy-8-chloro-4- tetralone 2- 2-carbethoxyethyl) -5-hydroxy-7-methyl-8-chloro- 4-tetralone 2- (Z-carboxyethyl) -5-hydroxy-7-isopropyl-S-chloro- 4-tetralone 2- (2-ca1'boxyethyl) -5hydroxy-7,8-diethyl-4-tetralone 2- (2-carbethoxyethyl) -5-propoxy-8-methylamino- 4-tetralone 2- 2-carbobenzyloxyethyl -5-benzyloxy-8-chloro- 4-tetralone 2- 2-carboxypropyl -S-hydroxy-S-chloro-4-tetralone 2- 2-carboxybutyl -S-hydroxy-8-chloro-4-tetralone 2- Z-canbob enzyloxyethyl -5-methoxy-7-amino- 8-chloro-4-tetralone 2- Z-carbobenzyloxyethyl) -5methoxy-7-ethyl-8-chloro- 4-tetralone 2- Z-carbobenzyloxyethyl -5-methoxy-7-methyl-8-chloro- 4-tetralone 2- Z-carboxyethyl) -5-hydroxy-7-dimethylamino-8-chloro- 4-tetralone 2- Z-carboxyethyl -7, 8-dimethyl-4-tetralone 2- (Z-canboxyethyl -5-hydroxy-8-chloro-4-tetralone l-methyl-Z- Z-carboxyethyl) -5-methoxy-8-chloro- 4-tetralone 1-ethyl-2 2-c arboxyethyl -5-rnethoxy-8-chloro- 4-tetralone 1-propyl-2-(Z-carboxyethyl) -5-rneth0xy 8-chlor0- 4-tetralone 1-methyl-2- (Z-carb oxypropyl) -5-methoxy-8-chloro- 4-tetralone 2- 2-carboxyethyl -5-hydroxy-8-methyl-4-tetralone 2- (Z-carboxyethyl -5-hydroxy-7, 8-dimethy1-4-tetralone l-propyl-Z- 2-carb oxyethyl -5 -hydroxy-8-chloro- 4-tetralone 2- Z-cyanoethyl -5-methoxy-8-methyl4-tetralone 2- 2-carb oxyethyl) -5-methoxy-7-methyl-8-chloro- 4-tetralone 2- 2-carbethoxyethyl -5,7-dimethoxy-4-tetralone 2- 2-carbobenzyloxyethyl -5-hydroxy-7-isopr0pyl- 4-tetralone 2- 2-carbomethoxyethyl -5-benzyloxy-8-amino- 4-tetralone 2- (2-carbomethoxyethyl) -5-propoxy-8-propyl-4-tetralone 2- (Z-carbomethoxyethyl -5-hydroxy-4-tetralone 1-methyl-2- Z-carbomethoxyethyl) -S-methoxy- 4-tetralone 1-ethyl-2- Z-carbomethoxyethyl -5-methoxy-4-tetralone 1-propyl-2-( 2-carbomethoxyethyl) -5-methoxy-4-tetralone 2- 2-carbobenzyloxyethyl) -5-hydr0xy-8-methyl- 4-tetralone 2- Z-carb obenzyloxyethyl -5-methoxy-4-tetralone 1-methyl-2- (Z-carbobenzyloxyethyl) -5-hydroxy- 4-tetralone l-propyl-Z- Z-carb ob enzylox yethyl) -5 -hydroxy- 4-tetralone In the above table, Me=CH Et=C H Pr- C H Ac 'acetyl.

These acids are converted to corresponding lower alkyl or benzyl esters by conventional procedures.

In the case of both oxidation procedures the acidification is effected by means of acetic acid and the product is extracted into n-butanol and recovered therefrom by evaporation.

EXAMPLE XXXV III Methyl, ethyl and propyl esters of (S-methoxybenozyl) acetic acid To a mixture of 16.6 g. (0.3 mole) of methyl 3-methoxybenzoate and g. (0.2 mole) of sodium hydride (48% dispersion in oil) in 300 ml. of dry dimethylformamide is added a solution of 8.0 g. of methyl acetate in 150 ml. of dry dimethylformamide dropwise with stirring at room temperature during a period of 4 hours. The mixture is then stirred for an additional two hours, after which it is acidified slowly with glacial acetic acid. The acidified mixture is poured into excess water which is next extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and then evaporated under reduced pressure to an oil. The residual oil is washed with hexane and distilled in vacuo to obtain 10.57 g. of the methyl ester product, B.P. 128-131 C./ (0.5 mm.), n =1.5428. Infrared analysis shows characteristic peaks at 5.73 and -5.92,u. Elemental analysis gives the following results:

Calcd. for C H O (percent): C, 63.45; H, 5.81. Found (percent): C, 63.28; H, 5.89.

The ethyl and propyl esters are prepared in the same manner (but heating at 50 C. for 15 minutes to insure complete reaction) using ethyl or propyl acetate in lieu of methyl acetate.

EXAMPLE XXXIX t-Butyl ester of (3-methoxybenzoyl) acetic acid To a stirred suspension of sodamide in liquid ammonia (prepared from 11.5 g. of sodium in 400 ml. of liquid ammonia) is added .54 g. of t-butyl acetate in 50 ml. of dry ether followed by a solution of 41.5 g. of methyl 3-methoxybenzoate in 50 ml. of dry ether. The ammonia is then replaced by 100 ml. of ether and the mixture refluxed for 2 hours. After standing at room temperature for 12 hours, the mixture is poured into 400 ml. of ice water containing 28.8 ml. of acetic acid. The mixture is then extracted with ether, the etherate Washed with 2% sodium bicarbonate solution and then dried over anhydrous sodium sulfate. After removal of the other at reduced pressure, the residual oil is distilled in vacuo to obtain 33.5 g. of product, B.P. 126128 (0.3 mm.). Infrared absorption of the product shows characteristic maxima at 5.75 and 5.90.

EXAMPLE XL Ethyl 3-carbomethoxy-3-(3-methoxybenzoyl) propionate Method A.To a suspension of 26 g. of sodium hydride in 250 ml. of dry dimethylformamide is added dropwise with stirring at room temperature a solution of 108 g. of the Example XXXVIII methyl ester in 250 ml. of dry dimethylformamide over a period of 45 minutes. The mixture is stirred for an additional minutes and there is then added dropwise with stirring a solution of 104 g. of ethyl bromoacetate in 250 ml. of dry dimethylformarnide. The mixture is allowed to stand for 12 hours and is then evaporated under reduced pressure. The residual oil is dissolved in chloroform and the solid sodium bromide filtered. The chloroform solution, after waterwashing and drying over sodium sulfate, is evaporated and the residual oil distilled in vacuo to obtain 112.5 g. of product, B.P. l82-188 C. (1.4-1.5 mm.). Infrared analysis of the product shows characteristic peaks at 5 .75

and 5.91 microns. Elemental analysis gives the following results:

Calcd. for C H O (percent): C, 61.21; H, 6.17. Found (percent): C, 61.39; H, 6.23.

Ethyl and propyl 3-carbethoxy-3-(3-methoxybenzoyl) propionate are prepared in similar fashion.

Method B.To a mixture of 29 g. of methyl 3-methoxybenzoate and 15 g. of sodium hydride in 75 ml. of dry dimethylformamide is added a solution of 19 g. of dimethyl succinate in 175 ml. of the same solvent dropwise with stirring at room temperature during 12-14 hours. The mixture is carefully acidified with 25 ml. of acetic acid and stirred at room temperature for an additional 3 hours. The filtered reaction mixture is next evaporated to a residue consisting of an oil and solid which is treated with ether to dissolve the oil. The ether solution is filtered and evaporated under reduced pressure to yield 18.29 g. of dimethyl a-(3-methoxybenzoyl) succinate, B.P. 162.9 C. (0.4-0.5 mm.). Infrared analysis of the product shows characteristic peaks at 5.75 and 5.90 microns. Elemental analysis gives the following results:

Calcd. for C H O (percent): C, 59.99; H, 5.75. Found (percent): C, 59.91; H, 5.79.

In similar manner, the corresponding diethyl, dipropyl and di-t-butyl esters are prepared.

EXAMPLE XLI Ethyl 3 -carbo-t-butoxy-3 3 -methoxybenzoyl) propionate A mixture of 15.8 g. of the product of Example XXXIX 10.5 g. of ethyl bromoacetate and 3.02 g. of sodium h-ydride in 130 ml. of dimethylformamide is treated as in Method A of Example XL to obtain this product as a yellow oil. Infrared analysis of the product shows characteristic peaks at 5.75 and 590g. The product is used without distillation in the procedure of Example XLIV to produce ethyl 3-[carbo-t-butoxy-3-(2- cyanoethyl -3- 3-methoxybenzoyl) -propionate.

EXAMPLE XLII Diethyl 3-carbethoxy-3- 3-methoxybenzoyl) adipate To a mixture of 102 g. of diethyl a-(3-methoxybenzoyl)succinate in 250 ml. of dioxane and 10 ml. of a 35% solution of benzyltrimethylammonium hydroxide in methanol maintained at 50 C. is added 167 g. of ethyl acrylate in one portion with stirring. Heating and stirring are continued for 30 minutes, after which 10 ml. of glacial acetic acid is added. The mixture is evaporated under reduced pressure to a dark oil which is distilled in vacuo to yield 80.5 g. of the diethyl ester product, B.P. 197 C. (0.1-0.2 mm.), n =1.5043. Infrared analysis shows characteristic peaks at 5.76 and 5.92 Elemental analysis gives the following results:

Calcd. for C H O (percent): C, 61.75; H, 6.91. Found (percent): C, 61.64; H, 6.90.

Dimethyl and dipropyl /3-carbomethoxy-3-(3-methoxy benzoyl)adipate are prepared in similar fashion.

EXAMPLE XLHI Diethyl 3-carbo-t-butoxy-3-(3-methoxybenzoyl)adipate The product of Example XLI a yellow oil, is dissolved in ml. of t-butanol containing 0.75 g. of potassium tbutoxide and 19 g. of ethyl acrylate. The mixture is refluxed for 1.3 hours and then concentrated under reduced pressure to obtain the adipate ester product, a yellow viscous oil, which is used without distillation in the procedure of Method B of Example XLV.

EXAMPLE XLIV oz- 3-methoxybenzoyl -oz- 2-cyanoethyl) succinic acid diethyl ester This compound is prepared according to the procedure of Example XLII using acrylonitrile or p-bromopropioni- 37 trile in lieu of ethyl acrylate. The product is vacuum distilled at 212-218 C. (0.45 mm. Hg). This product is hydrolyzed and decarboxylated to 3-(3-methoxybenzoyl)adipic acid by refluxing in aqueous acetic acid containing sulfuric acid by the procedure of Method A of Example XLV. Corresponding esters are prepared in the usual manner.

EXAMPLE XLV Diethyl 3-(3-methoxybenzoyl) adipate Methd.A mixture of 25 g. of diethyl-3-carbethoxy- 3- (3-methoxybenzoyl)adipate in 30 ml. of acetic acid, 10 ml. of concentrated sulfuric acid and 10 ml. of water is refluxed for 36 hours. The mixture is then poured into excess water and extracted with chloroform, the extract dried and evaporated under reduced pressure to an oil. The oil is dissolved in a mixture of 50 ml. of ethanol, 1 liter of ethylene dichloride and 6 ml. of concentrated sulfuric acid and refluxed for 12 hours. The mixture is then poured into water. The ethylene chloride layer is separated, dried and evaporated in vacuo to an oil which is distilled to obtain 5.5 g. of product, B.P. l'69-l72 C. (0.05 mm.), It =1.5092. Elemental analysis gives the following results:

Calcd. for C H O (percent): C, 64.27; H, 7.19. Found (percent): C, 64.09; H, 7.19.

In similar fashion, the dimethyl and dipropyl esters are prepared.

Method B.The product of Example XLIII a yellow viscous oil, is refluxed in 120 ml. of dry xylene containing 3.0 g. of p-toluenesulfonic acid and cooled and extracted with water. The xylene solution, after drying, is concentrated under reduced pressure and the residual oil vacuum distilled to obtain 6.8 g. of product.

There is also obtained 5.86 g. of the enol lactone:

o 0 H l=:/\/C 2 z 0 I OCH3 i) a red oil, which on infrared absorption analysis showed a maximum at 5.58 4.

As is recognized by those in the art, the product of this example is a racemic compound, DL-3-(3-methoxybenzc=yl)adipic acid diethyl ester which, as the free acid, lends itself to resolution into its optical active forms by salt formation with optically active bases such as brucine, cinchonine, cinchonidine, morphine and the like to form diasteroisomers. Such procedures are well known to those skilled in the art. Of course, the optically active forms (antipodes) after separation, may be converted one to the other, as desired, by racemization and resolution. The present compound, in one of its optically active forms, is racemized by treating it with a-strong base in solvent, e.g. sodium hydride, hydroxide or alkoxide in a lower alkanol. After racemization, the desired optical form may be resolved and the procedure repeated to produce more of the desired optical form from its antipode.

EXAMPLE XLVI Employing the procedure of Example XXXVIII the following compounds are prepared from corresponding starting compounds. Those compounds having an active hydrogen require the use of an additional mole of sodium hydride.

methylbenzoylacetate ethyl (2-ethyl-5-hydroxybenzoyl) acetate methyl 2-(S-methoxybenzoyl)propionate methyl 2-(5methoxybenzoyl)butanoate methyl 2-(S-methoxybenzoyl)pentanoate methyl (2-chloro-5-methoxybenzoyl)acetate methyl (2-dimethylamino-S-methoxybenzoyl)acetate methyl (Z-amino-S-methoxybenzoyl) acetate methyl (2-acetamido-S-methoxybenzoyl)acetate ethyl (5-hydroxybenzoyl)acetate ethyl (Z-methoxybenzoyl) acetate ethyl (3-hydroxybenzoyl)acetate ethyl (Z-methyI-S-hydroxybenzoyl)acetate ethyl (2,3-dimethyl-5-hydroxybenzoyl)acetate ethyl (3-isopropyl-S-hydroxybenzoyl) acetate ethyl (2,3-diethyl-S-hydroxybenzoyl) acetate ethyl (S-benzyloxybenzoyl) acetate ethyl (3-methyl-5-hydroxybenzoyl) acetate ethyl (3-dimethylamino-5-hydroxybenzoyl)acetate methyl (2,3-dimethylbenzoyl)acetate ethyl 2-(3,5-dime-thoxybenzoyl) acetate ethyl 2-(2,3-diethyl-5-ethoxybenzoyl)acetate ethyl 2-(3-isopropyl-S-ethoxybenzoyl) acetate methyl 2-(2-methylamino-5-methoxybenzoyl) acetate methyl 2-(3-ethyl-5-methoxybenzoyl)acetate ethyl 2-(2-methoxy-S-benzyloxybenzoyl) acetate ethyl 2-(2-propyl-5-prop0xybenzoyl)acetate ethyl 2-(3-trifluoromethyl-S-methoxybenzoyl)acetate ethyl 2-( 3-acetoxy-5-methoxybenzoyl) acetate propyl 2-(3-propoxybenzoyl) acetate benzyl 2-(2-chloro-S-methoxybenzoyl) acetate ethyl 2-(3-benzyloxybenzoyl) acetate ethyl 2-(3-amino-5-benzyloxybenzoyl) acetate ethyl 2- 3-propyl-5-methoxybenzoyl) acetate ethyl 2-(2-isopropyl-3-ethyl-5-methoxybenzoyl) acetate benzoyl 2-(2-methoxy-5-ethoxybenzoyl) acetate benzyl 2-(2-chloro-3-methyl-S-methoxybenzoyl) acetate ethyl 2-(2-chloro-3-dimethylamino-5-methoxybenzoyl) acetate methyl 2-(2-chloro-4-acetamidobenzoyl)acetate methyl 2-(2-chloro-3-acetamido-S-methoxybenzoyl) acetate methyl 2-(2,3-ditrifiuoromethyl-S-methoxybenzoyl) acetate methyl 2-(2-methyl-3 -propionoxybenzoyl) acetate ethyl 2-(2-trifiuoromethyl-3,S-dibutoxybenzoyl) acetate ethyl 2-(2-trifluoromethyl-3-ethylamino-5-methoxybenzoyl)acetate ethyl 2-(3-butyrylamidobenzoyl)acetate ethyl 2-(2-chloro-3 -acetoxy-5-ethoxybenzoyl) acetate ethyl 2-(2-chloro-3,5-dihydroxybenzoyl) acetate ethyl 2-(3-acetamido-S-hydroxybenzoyl)acetate ethyl 2-(3-trifluoromethyl-S-hydroxybenzoyl)acetate EXAMPLE XLVII The following carbalkoxybenzoyl propionates are prepared from corresponding benzoyl acetates by reaction with a-haloacetic acid esters according to the procedure of Method A of Example XL, as well as by the procedure of Method B, Example XL.

ethyl B-carbomethoxy-3-benzoylpropionate methyl 3-carbethoxy-3-(Z-ethyl-S-methoxybenzoyl) propionate methyl 3-carbomethoxy-3-(3-methoxybenzoyl) butanoate 1 methyl 3-carbomethoxy-3-(3-methoxybenzoyl) pentanoate 1 methyl 3-carbomethoxy-3-(3-methoxybenzoyl) hexanoate 1 methyl 3-carbomethoxy-3-(2-chloro-5-methoxybenzoyl) propionate methyl 3-carbomethoxy-3-(Z-dimethylamino-S-methoxybenzoyl)propionate benzyl 3-carbomethoxy-3-(2-acetamido-5-methoxybenzoyl)propionate benzyl 3-carbomethoxy-3-(2-acetamido-5-methoxybenzoyl)propionate ethyl 3-carbethoxy-3-(3-methoxybenzoyl)propionate ethyl 3-carbethoxy-3-(2,3-diethyl-5 methoxybenzoyl) propionate ethyl 3-carbethoxy-3-(3-isopropyl-S-methoxybenzoyl) propionate 39 ethyl 3-carbethoxy-3-(Z-methyl-S-ethoxybenzoyl) propionate ethyl 3-carbethoxy-3-(3-dimethylamino-S-propoxybenzoyl)propionate methyl 3-carbomethoxy-3-(2,3-dimethylbenzoyl) propionate ethyl 3-carbethoxy-3- 3-methoxybenzoyl) propionate ethyl 3-carbethoxy-3-(Z-methyl-S-methoxybenzoyl) propionate ethyl 3-carbethoxy-3-(4-methyl-S-methoxybenzoyl) propionate ethyl 3-carbethoxy-3-(2,3-dimethyl-S-methoxybenzoyl) propionate ethyl 3-carbethoxy-3-(3-benzy1oxybenzoyl)propionate ethyl 3-carbethoxy-3- 3,5-dimethoxybenzoyl) propionate ethyl 3-carbethoxy-3-(2,3-diethyl-5-ethoxybenzoyl) propionate ethyl 3-carbethoXy-3-(3-isopropyl-5-ethoxybenzoyl) propionate methyl 3-carbomethoxy-3-(Z-methylamino-5-methoxybenzoyl)propionate methyl 3-carbomethoxy-3-(3-ethyl-5-methoxybenzoyl) propionate ethyl 3-carbethoxy-3-(2-methoxy-S-benzyloxybenzoyl) propionate ethyl 3-carbethoxy-3-(2-propyl-5-prop0xybenzoyl) propionate ethyl 3-carbomethoxy-3-(3-trifluoromethyl-S-methoxybenzoyl) propionate ethyl 3-carbomethoxy-3-(3-acetoxy-S-methoxybenzoyl) propionate propyl 3-carbomethoXy-3-(3-propoxybenzoyl) propionate benzoyl 3-carbomethoxy-3-(2-chloro-5-methoxybenzoyl) propionate ethyl 3-carbomethoXy-3-(3-benzoyloxybenzoyl) propionate ethyl 3-carbomethoxy-3-(3-amino-S-benzyloxybenzoyl) propionate ethyl 3-carbomethoxy-3-(3-propyl-5-methoxybenzoyl) propionate ethyl 3-carbomethoxy-3-(2-isopropyl-3-ethy1-5-methoxybenzoyl) propionate benzyl 3-carbethoxy-3-(3-methoxy-5-ethoxybenzoyl) propionate benzyl 3-carbeth0xy-3-(2-chloro-3-methyl-5-methoxybenzyl) propionate ethyl 3-carbethoxy-3-(2-chloro-3-dimethylamino-5- methoxybenzoyl) propionate methyl 3-carbethoxy-3-(2-ch1oro-4-acetamidobenzoyl) propionate methyl 3-carbomethoxy-3-(2-chloro-3-acetamido-5- methoxybenzoyl)propionate methyl 3-carbomethoXy-3-(2-ditriflu01'omethyl-5- meth oxyb enzoyl) propion ate methyl 3-carbomethoxy-3-(2-methy1-3-propionyloxybenzoyl)propionate ethyl 3-carbethoxy-3-(2-trifluoromethyl-3,S-dibutoxybenzoyl) propionate ethyl 3-carbethoxy-3-(Z-trifluoromethyl-3-ethylamino- S-methoxybenzoyl propionate ethyl 3-carbethoxy-3-(3-butyry1amidobenzoyl) propionate ethyl 3-carbethoxy-3-(2-chloro-3-acetoxy-5-ethoxybenzoyl)propionate ethyl 3-carbethoxy-3(2-chloro-3,S-dihydroxybenzoyl) propionate ethyl 3-carbethoxy-3-(3-acetamido-S-hydroxybenzoyl) propionate ethyl 3-carbethoxy-3-(3-trifluoromethyl-S-hydroxybenzoyl) propionate Tl1e higher benzoyl alkanoates, e.g. butanoate, pentanoato and hexanoate, are prepared from the next lower homolog by the procedure of Method A, Example XL.

EXAMPLE XLVIII The following compounds are prepared from the prod nets of Example XLVII by the procedure of Examples XLIV and XLII using corresponding [i-bromo or a,[3-unsaturated esters or nitriles.

adipate diethyl 3 carbethoxy 3-(4-methyl-5-methoxybenzoyl) adipate diethyl 3 carbethoxy-3-(2,3-dimethyl-S-methoxybenzoyl) adipate diethyl 3 carbethoxy 3-(3-isopropyl-S-methoxybenzoyl) adipate diethyl 3 carbethoxy 3-(2,3-diethyl-5-methoxybenzoyl) adipate diethyl 3-carbethoxy-3-(3-benzyloxybenzoyl) adipate diethyl 3-carbeth0Xy-3- 3,5 -dimethoxybenzoyl) adipate diethyl 3 car-bethoxy 3 (2,3-diethyl-5-ethoxybenzoyl) adipate diethyl 3 carbethoxy 3-(3-isOpropyl-S-ethoxybenzoyl) adipate dimethyl 3 carbomethoxy-3-(Z-methylamino-S-methoxybenzoyl) adipate dimethyl 3 carbomethoxy-3-(3-ethyl-5-methoxybenzoyl) adipate diethyl 3 carbethoxy-3 (Z-methoxy-S-benzyloxybenzoyl) adipate diethyl 3 carbethoxy 3 (2-propyl-5-propoxybenzoyl) adipate diethyl 3 carbethoxy 3-(3-trifluoromethyl-5-methoxybenzoyl) adipate diethyl 3 carb0methoXy-3-(3-acetoxy-S-methoxybenzoyl) adipate dipropyl 3-carbomethoxy-3- 3-propoxybenzoyl adipate dibenzyl 3-carb0methoxy-3-(2-chloro-5-meth0xybenzoyl) adipate diethyl S-carb omethoxy-3-(3-benzyloxybenzoyl) adipate diethyl 3-carbomethoxy-3-(3-amino-5-benzyloxybenzoyl) adipate diethyl 3 carbomethoxy-3-(3-propyl-5-methoxybenzoyl) adipate diethyl 3-carbomethoxy-3-(2-isopropy1-3-ethyl-5-methoxybenzoyl) adipate dibenzyl 3 carbethoxy 3-(2-methoxy-S-ethoxybenzoyl) adipate dibenzyl 3 carbethoXy-3-(2-ch1oro-3-methyl-5-methoxybenzoyl) adipate diethyl 3 carbethoxy 3 (2-chloro-3-dimethylamino-5- methoxyb enzoyl) adi pate dimethyl 3 carbethoxy-3-(2-chloro-4-acetaminobenzoyl) adipate dimethyl 3 carbomethoxy 3 (2-chloro-3-acetamid0-5- methoxybenzoyl) adipate 

